Biomedical Sciences Research Highlights

Department of Biology

• Dr. Dale Casamatta

  Dr. Dale Casamatta

  Microbiology Research/Ecology Research

   

  Dr. Casamatta’s research interests revolve around aquatic ecology and systematics, both of which deal largely with algae in general, and specifically with cyanobacteria (blue-green algae).

   

  One of his chief research foci is in biodiversity and phylogenetic (evolutionary) relationships amongst the cyanobacteria.  The laboratory is using a library of cyanobacterial strains from around the world, coupled with extensive sampling of local environment. Employing morphological (cell dimensions, divisions, ultra-structure, folding patterns of the 16-23S internal transcribed spacer), ecological, and molecular (sequencing of the 16S rDNA gene) big datasets, the laboratory is elucidating phylogenetic relationships.  Casamatta’s lab and collaborators have erected two novel Families and numerous genera and species new to science during his tenure at UNF.  Lab members routinely sample myriad habitats from Florida in the quest to elucidate novel biodiversity and refine our knowledge of this ecologically and evolutionarily significant lineage.

   

  The Casamatta lab is also interested in exploring ecological questions involving cyanobacteria.  His team is currently exploring topics ranging from1) long-term anthropogenic impacts on aquatic habitats (via articulation of the algal community using both traditional methods and Next-Generation Sequencing Technology), 2) the nature of endemism vs. cosmopolitan distribution in microbes, and 3) seasonal and more long-term patterns of algal diversity and presence in Florida spring systems.   Dr. Casamatta’s research blends ecology, microbiology, evolution and molecular tools to address pressing issues in cyanobacterial research. 

   

  Highlighted Publications:

  In a pioneering study, Dr. Casmatta and an international team of scientists (Davidson et al. 2016) undertook a highly complex isotopic and proteomic analysis of the diet of COCY’ ant species (Colobopsis cylindrica clade).  In this study, the authors using proteomic analysis detected mostly low‐molecular weight proteins and peptides (8–15 kDa). Results seem to indicate the presence of membrane‐binding proteins and/or antimicrobial peptides.

   

  This article was chosen for Editor’s choice Article for Biotropica.

   

  In a recent study, Kilgore et al. (2018) performed molecular characterization of Geitleria appalachiana sp. nov. (Nostocales, Cyanobacteria) and formation of Geitleriaceae fam. nov. Sequence data for 16S rRNA and rpoC1 loci for the species were generated from field material using single filament PCR. Phylogenetic evidence indicates that Geitleria does not belong to any family in the Nostocales containing true–branching genera, i.e. Hapalosiphonaceae, Chlorogloeopsidaceae, and Symphyonemataceae, and consequently Geitleriaceae fam. nov. is established to contain this unique genus.

   

  Congratulations to Dr. Casamatta and his group of students for their accomplishments. 

• Dr. John Hatle

  Dr. John Hatle

  The Physiology of Aging

   

  Dr. Hatle’s recent work published in the Journal Experimental Gerontology sheds new light into diet, longevity and lifespan. His work shows that reducing dietary intake by ~30% increases lifespan in many animals, and also creates a hungry animal. One of the main hormonal signals of hunger is neuropeptide Y (known as NPF in insects).

   Previous work has shown that the NPY/F family of hormones can stimulate self-maintenance of cells (by stimulating autophagy). This should keep the cell’s biomolecules in their correct shape for longer, which promotes longevity. In a recent paper, Dr. Hatle’s group tested whether reduced diet and NPF can improve the maintenance of cellular proteins. Their results show that when diet is reduced and NPF levels are high, protein damage (i.e., carbonyls) is low. This study suggests that hunger signals participate in self-maintenance of cellular proteins.

   

  Congratulations to Dr. Hatle and his group of students for their accomplishments.

   

• Dr. Judy Ochrietor
  
  

  The Biomedical Sciences Program is pleased to highlight Dr. Judith Dr. Ochrietor’s Laboratory from the Department of Biology

   

   

  A leader in retinal degeneration, Dr. Ochrietor’s research over the last decade has revolved around mechanisms underlying neural cell metabolism in the retina. Her laboratory has been systematically dissecting the pathways involved with immunoglobulin superfamily of genes (Basigin) in the retina. The Basigin family members play pivotal roles in spermatogenesis, embryo implantation, neural network formation, pathogenicity and tumor progression. These genes are involved in cellular transport, extracellular matrix degradation and cell adhesion and the TCA cycle.

   

  In a recent study, Tokar et al. 2017 investigated the expression of Basigin gene members and monocarboxylate transporter-1 (MCT1) within the mammalian neural retina.  These results showed variant-specific expression pattern.  Expression was seen with MCT1 and Basigin variant-2, but not with Basigin variant-1, within the mouse pineal gland.  As a druggable target, these differential expression of Basigin family members open up novel opportunities for therapeutic intervention for numerous diseases ranging from cancer, infectious diseases, inflammation and age-related disorders.

   Recent  Presentations:

   

   Judith D. Ochrietor, Kyle B. Russell, Kyle McBride, Randall Maniccia, and Josephine M. Brown. Basigin gene products may contribute to the immunological aspects of diabetic retinopathy. Poster presentation at the 50^th Miami Winter Symposium “Diabetes: Today’s Research, Tomorrow’s Therapies.” Miami, Florida, January 2017

    

  Judith D. Ochrietor, Christopher J. Gilbert**, and Joseph D. Fong*. Basigin gene products associate with MCT1, MCT2, and MCT4 in neural tissues. Poster presentation at the Cell Biology of Degeneration and Repair in the Nervous System conference, Philadelphia, PA, December 2017

   

  Judith D. Ochrietor and Josephine M. Brown*. Basigin (CD 147) associates with Toll-like receptor 4 via its transmembrane domain. Poster presentation at the American Society for Cell Biology meeting, Philadelphia, PA, December 2017

   

  Abigail D. Tompa** and Judith D. Ochrietor. A comparison of cell adhesion molecule expression in the olfactory bulbs of male and female mice. Poster presentation at the Florida Undergraduate Research Conference, Melbourne, FL, February 2018

   

  Hannah Watts** and Judith D. Ochrietor. Analysis of the expression of Basigin, Embigin, and Neuroplastin in the mouse olfactory bulb. Poster presentation at the Florida Undergraduate Research Conference, Melbourne, FL, February 2018

   

  Judith D. Ochrietor and Ryan Al-Khatab**. LPS decreases the expression of metabolic transporters in mouse monocytes. Oral Presentation at the American Society for Cell Biology conference, San Diego, CA, December 2018

    

  Judith D. Ochrietor and Ryan Al-Khatab**. LPS decreases the expression of metabolic transporters in mouse monocytes. Poster presentation at the 2019 American Society for Biochemistry and Molecular Biology (Experimental Biology) conference Orlando, Florida, April 2019

   

  Ashton N. Ray** and Judith D. Ochrietor. Homogenized mouse neural retina extracts stimulate an immune response in the mouse monocyte RAW 264.7 cell line. Poster presentation at the 2019 American Society for Biochemistry and Molecular Biology (Experimental Biology) conference Orlando, Florida, April 2019

   

  Alicia Gonzalez* and Judith D. Ochrietor. Basigin gene products associate to form a novel cell-adhesion system used to maintain a metabolic cytoarchitecture and potentially stimulate an immune response in the neural retina. Poster presentation at the 2019 American Society for Biochemistry and Molecular Biology (Experimental Biology) conference Orlando, Florida, April 2019

   

  Abigail D. Tompa* and Judith D. Ochrietor. The Basigin-variant-2 binding domain in the Ig0 domain of Basigin-variant-1 stimulates an immune response in the mouse monocyte RAW 264.7 cell line. Poster presentation at the 2019 American Society for Biochemistry and Molecular Biology (Experimental Biology) conference Orlando, Florida, April 2019

   

   *graduate student; **undergraduate student

   

  Congratulations to Dr. Ochrietor , collaborators and her group of students for their accomplishments.

   

   

   

• Dr. Fatima Rehman

  Dr. Fatima Rehman

  Cellular & Molecular Biology Research

   

  Dr. Rehman’s research interests include visualization and understanding of molecular and cellular processes during normal and disease states using cutting edge time-lapse, confocal, laser scanning and holographic microscopy techniques in combination with molecular pathway analyses. The laboratory is using clinical specimens from patients as well as in animal models and in primary hepatocytes cultured in vitro to better understand and alleviate the cell cycle changes associated with the process of aging.

   

  In a recent study (Kang et al. 2019), Dr. Rehman collaborated with Dr. Nguyen at the Mayo clinic in developing improved procedures and guidelines for liver transplantation to allow more patients to receive successful transplants. In this study, using a state of the art LifePort system, Dr. Rehman and collaborators were able to simulate and characterize Small-for-size grafts using monosegments from a discarded Deceased-donor human liver. Small-for-size grafts in adult transplant recipients have an elevated risk of graft failure, limiting its application in clinical patients. This model provides a rationale for developing an effective preclinical platform for molecular investigation.

   

  In an elegant recent study (Chen et al. 2019), Dr. Rehman and collaborators presented a novel method for visualizing the regeneration process using a mouse line with a Fluorescence ubiquination-based cell cycle indicator (Fucci) that generates different fluorescence markers for each cell cycle stage. The Fucci mice allow for direct visualization of hepatocellular regeneration in liver tissues, in vivo and ex vivo, using two-photon laser scanning microscopy. The Fucci model is a powerful tool for advanced studies of liver regeneration as cell cycle change could be visualized within a few hours in regenerating livers of the Fucci mice.

   

  Long-term interest from the laboratory revolves around testing whether Gamma aminobutyric acid (GABA) supplement could protect the liver from injury and protect or enhance its regeneration capability as it ages. Acute liver failure from severe liver injury is a critical condition associated with high mortality.  Recent results (Hata et. al, 2019) support this premise. Results showed that preemptive treatment with GABA protected against severe acute liver injury in mice via GABA-mediated STAT3 signaling. These results suggest that pretreatment with GABA may be a useful approach to optimize marginal donor livers before transplantation.

   

  An additional focus in the laboratory revolves around studying the aberrant cell cycle in cancer progression. Using breast and oral cancers, clinical and molecular studies are being performed to facilitate identification of protein biomarkers for novel diagnosis, prognosis and treatment efficacy.

  Congratulations to Dr. Rehman and her group of students for their accomplishments.

   

• Dr. Frank Smith

  Dr. Frank Smith

  Evolutionary Developmental Biology

  
  

  Smith et al. 2018 (Evodevo)

  The evolution of complex brains is one of the most mysterious issues in biology. Complex brains are found in vertebrates and arthropods, two very distantly related lineages. The brains of these animals are composed of three main regions, and hence are referred to as tripartite brains. In vertebrates, these regions are referred to as the forebrain, midbrain, and hindbrain. In arthropods, these regions are referred to as the protocerebrum, deutocerebrum, and tritocerebrum.

   

  Surprisingly, very similar mechanisms control development of the tripartite brains of vertebrates and arthropods. This led to the hypothesis that the ancestor of vertebrates and arthropods already had a complex tripartite brain. Rather surprisingly, this hypothesis suggests that complex brains evolved very early in animal evolution, given that the ancestor of vertebrates and arthropods lived approximately 600 million years ago.

   

   Recently, researchers discovered that the mechanisms that control brain development in vertebrates and arthropods are present in hemichordates, relatives of vertebrates that lack brains. This result presented the possibility that the mechanisms that control brain development in vertebrates and arthropods are actually more ancient than tripartite brains. Dr. Smith and his group tested this hypothesis by investigating brain development in the tardigrade Hypsibius exemplaris, a close relative of arthropods.

   Their research indicates that tardigrades have a simple brain composed of just a protocerebrum, and that the deutocerebrum and tritocerebrum evolved in the arthropod lineage after it split from the tardigrade lineage. Additionally, the results reveal that, although tardigrades have a simple brain, the developmental mechanisms that were originally identified in vertebrates and arthropods are present in tardigrades.

   

  This work strongly suggests that the ancestor of arthropods and vertebrates did not have a complex tripartite brain, but the mechanisms that control brain development in these animals was already present, although serving a different purpose. Therefore, the complex tripartite brains of vertebrates and arthropods appear to have evolved independently by recruitment of the same ancestral developmental mechanism.       

   

  Coldspring Harbor Protocols .

   

   Dr. Frank Smith (Smith, 2018) developed an in situ hybridization protocol that enables the visualization of mRNA expression patterns in tardigrade embryos. He also helped develop a protocol that enables visualization of protein expression patterns in tardigrade embryos (Smith and Gabriel, 2018).

   

  Meeting Abstracts: Undergraduate presenters are highlighted in bold.

  I. 2019 Society of Integrative and Comparative Biology

   

  CUMMING, M*; SMITH, FW. A Novel Developmental Mechanism Patterns Legs in Tardigrades.

   

  *Winner Best Student Poster Presentation in the Division of Evolutionary Developmental Biology

   

  NOLTE, P; SMITH, FW. Expression Patterns of Gut Genes During Development in Tardigrades.

   

  II. 2019 Pan-American Society for Evolutionary Developmental Biology

   

  CUMMING, M*; SMITH, FW. The miniaturization of tardigrade legs is correlated with the loss of proximal and intermediate appendage domains               

   

  *2nd place for Best Undergraduate Poster Presentation

   

   SMITH, FW. The developmental underpinnings of the miniaturized body plan of Tardigrada

   

  Congratulations to Dr. Smith and his group of students for their accomplishments.

   

• Dr. David Waddell

   

  Dr. David Waddell

  Molecular, cellular and genetic mechanisms of skeletal muscle atrophy

   

  Grants reviews:

   

  Dr. Waddell, Associate Professor from the Biomedical Sciences Program in the Biology Department has recently participated in the following study sections and grant reviews in the US, UK and Singapore (2017-current):

   

  Musculoskeletal, Oral, and Skin Sciences AREA Study Section (R15) ZRG1 MOSS D82 for NIH on February 16, 2017.

   

  Medical Research Council (MRC), United Kingdom

  Research and Innovation , August, 2017. 

  National Research Foundation (NRF) Competitive

  Research Programme (CRP),  Prime Ministers Office of Singapore, December, 2018.

   

  National Centre of the Replacement, Refinement and Reduction of

  Animals in Research (NC3Rs), United Kingdom Research and Innovation,  May, 2018. 

   

  Biotechnology and Biological Sciences Research

  Council (BBSRC), United Kingdom Research and Innovation,  March, 2018.

   

  Orthopedic, Skeletal Muscle, and Oral Sciences Study Section (ZRG1 MOSS D10) (SBIR/STTR grants) for NIH on June 13-14, 2019.

  Musculoskeletal, Oral, and Skin Sciences AREA Study Section (R15) ZRG1 MOSS D82 for NIH on June 14, 2019. 

  
  Skeletal Muscle and Exercise Physiology Study Section (2020/01 SMEP) for NIH on October 7-8, 2019. 

   

  Scientific Presentations:

  Dr. Waddell and his students participated at the Annual Experimental Biology Conference  in Orlando, FL April 4-7, 2019. His group of students presented their ongoing research.

   

  Undergraduate Posters from Experimental Biology Conference (undergraduate students from UNF are bolded; * Presented by):

   

  Aimee Cruikshank*,  Sarah Lynch and David Waddell. Ubiquitin Specific Peptidase 3 (USP3) is Expressed in Skeletal Muscle and is Upregulated in Response to Neurogenic Atrophy.

   

  Tala Tello*  and David Waddell. Identification and Characterization of TSSK6 Activating Co-Chaperone (TSACC) in Skeletal Muscle.

   

  Parker Irvin*,  Kelsey Patterson, and David Waddell. Identification and Characterization of Calcium Binding and Coiled Coil Domain 1 (Calcoco1) in Skeletal Muscle.

   

  Alexandra Arcaro*, Lillian Hewitt* , and David Waddell. Identification and Characterization of Homocysteine Responsive Endoplasmic Reticulum Resident Ubiquitin-like Domain Member 2 (Herpud2) in Skeletal Muscle.

   

  Ciara Golliher*, Anjelican DaSilva* , and David Waddell. Identification and Characterization of TNF Receptor Associated Factor 3 Interacting Protein 3 in Skeletal Muscle..

   

  Jack Kavanagh*,  Lisa Cooper, and David Waddell. Characterization of the Regulation of Family with Sequence Similarity 83 Member D (Fam83D) in Skeletal Muscle.

   

  Keri Wortherly*  and David Waddell. Identification and Characterization of Ovarian Tumor Protease Domain Containing 1 (OTUD1) in Skeletal Muscle.

   

  Adrianna White*  and David Waddell. F-box and WD-40 Domain Protein 5 (Fbwx5) and F-box Protein 44 (Fbxo44) are Expressed in Skeletal Muscle.

   

  Graduate Student Posters from Experimental Biology (Graduate students from UNF are bolded; * Presented by):

   

  Sydney Labuzan*  and David Waddell. Identification and Characterization of Protein Phosphatase Methylesterase (Ppme1) in Skeletal Muscle.

   

  Sarah Lynch*  and David Waddell. Identification and Characterization of 1700029J07RIK, a Novel Gene Expressed in Skeletal Muscle.

   

  Lisa Cooper*  and David Waddell. Dual Specificity Phosphatase and Pro Isomerase Containing 1 (Dupd1) is Upregulated During Skeletal Muscle Atrophy and is Differentially Expressed in MuRF1-null Mice.

   

  Anastasia Smith *  and David Waddell. Identification and Characterization of Allograft Inflammatory Factor-1 Like (Aif1L) in Skeletal Muscle.

   

  Publications:

  In an APSselect manuscript entitled “Dual-Specificity Phosphatase 4 (Dusp4) is Upregulated During Skeletal Muscle Atrophy and Modulates Extracellular Signal-Regulated Kinase (ERK) Activity”, the Waddell lab group in the Biology Department at the University of North Florida showed for the first time that Dusp4 is expressed in skeletal muscle and is upregulated during neurogenic muscle atrophy. Furthermore, the findings from this study show that Dusp4 binds to ERK1/2, but not p38 or JNK, in muscle cells and inhibits MAP kinase signaling and muscle cell differentiation. The results of this study strongly suggest that the MAP kinase signaling pathway may play an important role in the muscle atrophy cascade and that Dusp4 could be a potential druggable target for the prevention or treatment of muscle wasting associated with chronic disease states, such as cancer, cardiovascular disease, and Alzheimer’s, as well as, aging-associated muscle loss. 

   

   

  Congratulations to Dr. Waddell and his group of students for their accomplishments.

Department of Chemistry

• Dr. Brian Knuckley
  
  

  The Biomedical Sciences Program is pleased to highlight Dr. Bryan Knuckley’s Laboratory from the Department of Chemistry

  Dr. Knuckley’s (Chairman of Chemistry Department) research revolves around understanding the substrate specificity, physiological, and pathological roles of a family of proteins called the Protein Arginine Methyltransferases (PRMTs). The PRMTs catalyze methylation of arginine residues within proteins. Arginine methylation dysreguation of proteins plays a major role in the onset and progression of numerous human diseases (cardiovascular disease, neurodegenerative diseases, metabolic, muscular disorders and diverse cancers).  

   

  Arginine methylation is a common post-translational modification functioning as an epigenetic regulator of transcription, pre-mRNA splicing, DNA damage signaling, mRNA translation, cell signaling, and cell fate decision. The involvement of PRMTs in diverse pathways makes them attractive drug targets for various therapeutic areas. The Knuckley Lab is interested in developing novel methods to characterize the differences in substrate specificity within this family in a high-throughput fashion.

   

  In a recent elegant study (Mann et al. 2019), demonstrated the development of a chemical probe, based on a non-natural peptide sequence, which specifically labels PRMT1 over PRMT5 with high selectivity and sensitivity. The selectivity of the peptide portion provides the probe with a manner to distinguish between these two isozymes. The probe identified in this report a strong rationale for future biochemical experiments that may aid in distinguishing the role these isozymes in disease or under normal physiological conditions.

   

  In an earlier study, a plate-based Nonradioactive and sensitive method for screening multiple peptides was established (Nguyen et al. 2015). This facilitated rapid establishment of substrate specificity of PRMTs. This assay provides a timesaving, cost effective to traditional PTMT assays.

   

  Dr. Knuckley’s research also revolves around the catalytic mechanism of the guanidinium-modifying enzymes (GME) superfamily. A specific member of the GME family, the agmatine deiminase (AgD) is expressed in many pathogenic bacteria. Agmatine deiminase is responsible for converting agmatine to N-¬carbamoylputrescine with concurrent release of ammonia. This enzyme is believed to play a role in the acid resistance of these bacteria and enhance the innate immune response.

   

  Listeria monocytogenes is a Gram-positive food-borne pathogen that is capable of living within extreme environments (i.e. low temperatures and pH). This ability to survive in such conditions may arise, at least in part, from agmatine catabolism via the agmatine deiminase system (AgDS). This catabolic pathway utilizes an agmatine deiminase (AgD) to hydrolyse agmatine into N-carbamoylputrescine.

   

  In a study, (Soares and Knuckley, 2016) investigated the agmatine catabolism pathway via the agmatine deiminase system (AgDS) from Listeria monocytogenes. These are Gram-positive food-borne pathogen that is capable of living within extreme environments (low temperatures and pH). This ability to survive in such conditions may arise, at least in part, from agmatine catabolism via the agmatine deiminase system (AgDS). Their results show that for the first time that this pathway mechanism is implicated in the GME superfamily. These results can explain the failure of previously developed mechanism-based inactivators of AgDs against this orthologue.

   

  Dr. Knuckley’s findings provide a rationale for drug leads identification for multiple therapeutic areas.

  Congratulations to Dr. Knuckley, collaborators and his group of students for their accomplishments.

• Dr. Kenneth Laali

  Dr. Kenneth Laali

  Synthetic Method Development: Medicinal Chemistry & Drug Discovery

   

  With over 250 publications, Dr. Laali’s laboratory is at the forefront of Chemical Biology. With major interest in drug discovery for key therapeutic areas, Dr. Laali’s group and collaborators recently published a paper (Laali et al. 2018) describing anti tumor activity of a Library of Heterocyclic Curcuminoids.

  In this study, the research revolved around discovery of curcuminoid (CUR) compounds with antitumor activity.  A novel series of heterocyclic CUR-BF₂adducts and CUR compounds based on indole, benzothiophene, and benzofuran along with their aryl pyrazoles were synthesized.  Using computational docking studies, binding efficiency to cancer-related target proteins involved in specific cancers (HER2, proteasome, VEGFR, BRAF, and Bcl-2) was determined in comparison to known inhibitors.

   

  Series of compounds were identified with very good binding affinities, similar to, and even more favorable than those of known inhibitors. The indole-based CUR-BF₂ and CUR compounds and their bis-thiocyanato derivatives exhibited high anti-proliferative and apoptotic activity by in vitro bioassays against a panel of 60 cancer cell lines (NCI-60).

  The growth inhibitory activity was more specific against multiple myeloma (MM) cell lines (KMS11, MM1.S, and RPMI-8226) with significantly lower IC₅₀ values versus healthy PBMC cells. Further, these compounds also exhibited higher anti-proliferative activity in human colorectal cancer cells (HCT116, HT29, DLD-1, RKO, SW837, and Caco2) than the parent curcumin. Cancer cell specificity was inferred from significantly reduced cytotoxicity in normal colon cells (CCD112CoN and CCD841CoN).

   

  In another recent study (Laali et al. 2019), Dr. Laali and collaborators synthesized and tested the bioactivity of a series of deuterated curcuminoids (CUR). These compounds showed significant anti-proliferative activity in human colorectal cancer cells (HCT116, HT29, DLD-1, RKO, SW837, and Caco2). The deuterated CUR-BF₂ adducts versus non-deuterated analogues exhibited differential cytotoxic effects. In this report, structural studies (X-ray and DFT) and computational molecular docking studies comparing their inhibitory effects with known anticancer agents were also performed.

   

  These results provide novel therapeutic opportunities for specific cancers. In view of the known effects of CUR compounds in other diseases, the compounds described in the study may also aid in the discovery of therapeutics for multiple diseases.   These compounds are IP-protected by a Provisional US Patent application PR 2908.36.

   

  Congratulations to Dr. Laali and his research group for their accomplishments.

• Dr. Amy Lane
  
  

  The Biomedical Sciences Program is pleased to highlight Dr. Amy Lane’s Laboratory from the Department of Chemistry

   

  A leader in Chemical Biology, Dr. Lane’s research revolves around natural products (secondary metabolites) from marine microorganisms.

   

  Dr. Lane recently received the Henry Dreyfus Teacher-Scholar Award. Each year, this award recognizes approximately eight faculty members nationwide for accomplishments in teaching and research. The American Society of Pharmacognosy also recently recognized her as the 2019 Matt Suffness Awardee. This award recognizes one junior-stage investigator annually for contributions to the natural product field.

   

  Using a combined chemical-genetic approach, Dr. Lane’s research focuses on applying genome sequence information to guide the discovery of novel marine natural products as therapeutics for bacterial infections and cancer. Her group also elucidates the biosynthetic pathways by which marine microorganisms assemble these metabolites, providing novel enzymatic tools for the synthesis of complex natural products.

   

  In a recent study (Carey et.al, 2019), the Lane group developed an isotopic ratio outlier analysis (IROA) technique for study of actinomycete natural products. This approach utilizes ultra-high performance liquid chromatography-mass spectrometry (UHPLC/MS) global metabolomics to facilitate rapid recognition of novel metabolites from actinomycetes and environmental variables influencing metabolite production. This study revealed impacts of an iron chelator on the nocazine/XR334 diketopiperazine (DKP) pathway and other metabolic pathways in a model actinomycete. This study demonstrated IROA metabolomics as a powerful tool in the actinomycete natural product chemistry arsenal.

   

  In a recent review, (Borgman et al. 2019) outlined current state-of-the-art knowledge on microbial synthesis of structurally diverse 2,5-diketopiperazine (DKP) bioactive natural products. By understanding the unique enzymology provided by bacterial biosynthetic pathways, as highlighted in this review and research articles from the Lane group (James et al. 2016; Alqahtani et al. 2015), novel bioactive molecules have emerged for various therapeutic areas.

   

  In major collaborative efforts, Dr. Lane’s laboratory (Von Roemeling et.al, 2018) participated in developing an innovative computational-based drug discovery strategy. Using machine-based learning and functional assessment, inhibitors of the lipogenic enzyme stearoyl-CoA desaturase 1 (SCD1) were discovered. The lead compound was shown to have potent anti-tumor activity (sub-nanomolar range), with an excellent pharmacokinetic and toxicology profile. This work provides a unique platform for the discovery of novel drugs.

   

  Congratulations to Dr. Lane, collaborators and her group of students for their accomplishments.

College of Computing, Engineering & Construction

• Dr. Juan Aceros

  The Biomedical Sciences Program is pleased to highlight Dr. Juan Aceros’s Laboratory from the Electrical Engineering at the School of Computing  at College of Computing, Engineering & Construction.

   

  Dr. Aceros’s research interests revolve around fabrication of biomedical devices, Biomedical Sensors and Stimulators, Human Interface Devices,  assistive technologies, micro/nano fabrication and MicroElectroMechanicalSystems (MEMS).

   

  In a recent elegant study, Aceros and his collaborators (Fidias et al. 2019) developed a novel neurophysics approach to measure the content of the rectified motor evoked potential (MEP) induced by transcranial magnetic stimulation (TMS). Until recently this has been ambiguously assessed without the precision of energy calculation, which has misled data interpretation and misguided biomedical interventions. Results indicate a dramatic paradigm shift in analysis and interpretation of the content of the MEP. This innovative approach allowed unveiling that women exerted more bioenergy than men at the magnetic stimulations used in this study. These results strongly suggest revisitation of conclusions drawn from studies published elsewhere, assessing rectified EMG signals that have used ambiguous units.

   

  In a comprehensive recent review, Aceros and collaborators (Fraser et al. 2019) summarized current state of toy-related injuries including children with and without disabilities. Toy-related injuries have increased significantly in the past decade, in particular those related to ride-on toys. There are very limited pediatric safety studies regarding children with disabilities and modified ride-on toys.

   

  This extensive survey showed a gap in the literature concerning the susceptibility of children with disabilities to toy-related injuries, specifically in relation to ride-on toys and the repercussion surrounding such injuries. It is likely that such lack of data is due to the difficulty and costs associated with experimental validation. To address this, computer simulations could be used to provide preliminary data analysis.

   

  In a previous work using non-human primates Aceros and his collaborators (Barrese et al. 2016) investigated Signal attenuation of intracortical sensors for chronic neuroprosthetic applications. This work investigated the factors contributing to progressive signal decline by using scanning electron microscopy (SEM) to visualize structural changes in chronically implanted arrays and histology to examine the tissue response at corresponding implant sites.

   

  The results provided evidence that signal loss in microelectrode arrays (MEAs) is truly multifactorial. Gliosis occurs in the first few months after implantation but does not prevent useful recordings for several years. Progressive meningeal fibrosis encapsulates and lifts MEAs out of the cortex while ongoing foreign body reactions lead to progressive degradation of the materials. Oxygen radicals released by cells of the immune system likely mediate the degradation of these materials. These results provided a framework for future MEA designs through more durable insulation materials, more inert electrode alloys, and pharmacologic suppression of fibroblasts and leukocytes.

   

  
  

  Grants and Contracts Awarded (Select grants are shown)

  
  

  PI: Aceros, J. (2019-20): “Development of a National Institutes of Health R15 grant to study Remote Rehabilitation of Young Children with Cortical Visual Impairment (CVI)”. University of North Florida Faculty Development Grant.

   

  PI: Aceros, J. (2018-23): “Child-centered, team-based, interdisciplinary Bioengineering Summer Research Experience”. National Institutes of Health R25-NICHD. Note: NIH review produced a rare perfect “Impact Score 10”. 

   

  PI: Aceros, J. (2016-21): “Hands-On, Child-Centered, Interdisciplinary Team Design, Fabrication, and Testing of Adaptive Technology”. National Institute of Health (NICHD, 1R25HD087971-01).

  Patents 

  IMPLANTABLE WIRELESS NEURAL DEVICE 20140094674 (2014)

  WO/2012/126003

   

  Awards (Select awards are shown)

   

  • High-Impact Research Article Award (2015-16) by UNF Office of Research and Sponsored Programs
  • Nominated for the 2013 Brain Computer Interface (BCI) award sponsored by g-Tec Medical Engineering

   

   

  Highlighted Work and Media Coverage (Selected highlights) 

   

  • University of North Florida students create specialized toys for special kids, Florida Times Union, November 5 (2018). 
  • A toy workshop for kids with disabilities, CNN New Day, Dec 26, 2016. 
  • Students Build High-Tech Toys for Disabled Kids, US NEWS by Associated Press, Dec. 19, 2016.
  • Student-created toy initiative helps disabled children play, USA Today, October 29 (2015). 
  • Wireless, implanted sensor broadens range of brain research,”NIH News, March 19 (2013). 
  • Wireless option developed for brain-powered device, Science Daily, March 6 (2013). 
  • Yorkshire Pigs Control Computer Gear With Brain Waves, Wired, March 5 (2013). 
  • MEMS Microhotplates for Reliability Testing of Thin Films and Nanowires,” May 5, issue of Virtual Journal of Nanoscale Science & Technology (2008). 

   

   

  Congratulations to Dr. Aceros, collaborators and his group of students for their accomplishments.

   

• Dr. Sanjay P. Ahuja
  
  

  The Biomedical Sciences Program is pleased to highlight Dr. Sanjay Ahuja’s Laboratory from the School of Computing  at College of Computing, Engineering, and Construction.

  Dr. Ahuja established and directs the Cloud Computing Research Group (CCRG) at UNF. He was the Fidelity Information Services (FIS) Distinguished Professor of Computing Sciences from 2010-2014.

  A leader in big data analytics, Dr. Ahuja’s research revolves around Cloud and Fog computing, Internet of things, Cyber security, high performance computing, simulation and Genetic Algorithms.

  In a recent article, (Ahuja et al. 2018) describes how in recent years, Cloud Computing has emerged as a fundamental computing paradigm that has significantly changed the approach of enterprises as well as end users towards implementation of Internet technology. A new computing paradigm has been proposed by Cisco in early 2014 and termed 'Fog Computing'. Fog Computing otherwise known as Edge Computing is the integration of Cloud Computing and Internet of Things (IoT).

   

  Being located in close proximity to the IoT devices, the Fog assists with latency requirements of IoT related applications. It also meets the data processing needs of IoT devices, which are resource constrained by bringing computation, communication, control and storage closer to the end users. Recommendations in the areas of future research have strong implications to data analytics to biomedical sciences and genome research.

   

  In a further article, (Ahuja and Deval, 2018) evaluated four

  Infrastructure-as-a-service (IaaS) cloud services (Amazon EC2, Microsoft Azure, Google Compute Engine and Rackspace Cloud) in a vendor-neutral approach with regards to system parameter usage including server, file I/O and network utilization. Benchmarks established in the study provide a rationale for the selection of cloud platforms for specific tasks in big data analytics.

   

  Research in biomedical sciences is big data driven. Vast amounts of genome sequence information, chemical structures and single cell transcriptomes are available for datamining. Numerous bioinformatics and chemoinformatics tools are available on the cloud for efficient datamining. The benchmarks established by Dr. Ahuja’s research will greatly aid in biomedical sciences research at UNF.

   

  Congratulations to Dr. Ahuja, collaborators and his group of students for their accomplishments.

Brooks College of Health

• Dr. Andrea Y. Arikawa

  Dr. Andrea Y. Arikawa

  Translational Research in Diet and Nutrition

   

  Dr. Arikawa’s research spans basic and translational research in diet and nutrition.  A leader in nutritional science, Dr. Arikawa’s research revolves around the microbiome and dietary factors related to chronic diseases such as cancer, diabetes, inflammation and obesity.

   

  The potential health benefits of green tea polyphenols (GTP) have been extensively documented in the literature. However, the metabolic impact of chronic GTP intake on humans is unclear. In an elegant recent study, Zhou et al. 2019 performed liquid chromatography-mass spectrometry-based metabolomic analysis using feces and urine samples from postmenopausal female subjects taking a GTP supplement or placebo for 12 months. Results suggest extensive microbial biotransformation of GTP in humans.  GTP was shown to decrease the levels of microbial metabolites of aromatic amino acids, in the urine, but not in the secondary bile acids, and in feces. Chronic consumption of GTP did not alter the fecal microbiome as monitored by 16S rRNA gene sequencing. These results shed light into the role of microbial metabolism, in the beneficial health effects of green tea consumption in humans.

   

  In another study, Stallings-Smith et al. 2018 explored the association between polycyclic aromatic hydrocarbons (PAHs) and diabetes in order to determine whether effects are heterogeneous when examined by body mass index (BMI). A Cross-sectional data from 8664 participants were analyzed from the National Health and Nutrition Examination Survey for years 2005–2014. This study demonstrated a positive association with diabetes in response to high levels of exposure to PAHs in the U.S. These findings suggest the importance of strong environmental regulation of PAHs to protect population health.

  Breast cancer (BC) diagnosis often results in in weight gain and obesity along with sedentary behavior, which are associated with increased risk of BC recurrence and mortality.  It was hypothesized that weight loss would result in a statistically significant improvement in biomarkers associated with risk of breast cancer recurrence. It is important to determine whether a significant weight loss would lead to beneficial changes in biomarkers associated with cancer and/or cancer recurrence, and quality of life (QOL) in overweight and obese BC survivors.  To address this, Arikawa and collaborators (2018) investigated (ClinicalTrials.gov identifier: NCT02940470) in a parallel-arm randomized controlled weight loss pilot study. Twenty-one women were enrolled into the study and 20 completed all time points.

   

  The pilot study outcome show that overweight and obese BC survivors were able to adhere to a strict diet and exercise program, which significantly decreased body weight, increased fitness level, and improved biomarkers and QOL. This study suggests a need for larger randomized controlled trials to help breast cancer survivors achieve a sustainable weight loss and fitness level.

   

  Congratulations to Dr. Arikawa, her collaborators and students for their accomplishments.

• Dr. Chitra L. Balasubramanian
  The Biomedical Sciences Program is pleased to highlight Dr.  Chitra L. Balasubramanian’s laboratory in the Clinical & Applied Movement Sciences Department at the Brooks College of Health 

   

  Dr. Balasubramanian’s research goal is to enhance evidence-based practice in walking and balance rehabilitation for the elderly population and individuals with neurologic pathologies. Her overall research focusses on targeted assessment to assist in the development of efficient rehabilitation strategies for walking and balance improvement.

   

  Her laboratory utilizes novel ways to understand the neural control of movement using biomechanical, neurophysiologic and clinical measures. Their long-term goal is to design therapeutic strategies to improve walking and balance function.

   

  Dr. Balsubramanian is an internationally recognized scholar and made numerous presentations in the US, Canada, Europe, India, Japan and Singapore. Her outstanding research accomplishments have been recognized by Brooks Dean's Professorship Grants and by Brooks Rehabilitation Hospital’s Collaborative Grant funds.

   

  One of the highlights from her current research is her work focused on walking adaptability in individuals who have sustained a stroke. She and her colleagues clarified the term ‘walking adaptability’ in the literature and established a framework to assess walking adaptability (Balasubramanian et al. 2014). Since its publication in 2014, this paper has been steadily and increasingly cited (current google scholar citations = 63).

   

  She and her collaborators have continued their work on walking adaptability and in 2018  (Vistamehr et al. 2018) investigated Dynamic balance during walking adaptability tasks in individuals post-stroke. Kinematic data from fifteen individuals with post-stroke hemiparesis during steady-state forward and backward walking, obstacle negotiation, and step-up tasks were collected. Data from ten healthy adults were also collected and served as the control. Results indicate that improving paretic foot placement and ankle plantarflexor activity, particularly during obstacle negotiation is crucial.  These results provide important rehabilitation targets to enhance dynamic balance during post-stroke community ambulation.

   

   Further continuing this line of work, recently her team (Hawkins et al. 2019) investigated the walking adaptation of backward walking in post-stroke patients. Results show that the assessment of backward walking can unmask post-stroke walking impairments not detected during typical Forward walking. This suggests that backward walking should be assessed when determining readiness for home and community ambulation.

   

  Similar to this work in the post-stroke population, Dr. Balasubramanian, her team of collaborators along with UNF students are pursuing research projects currently studying backward walking in older adults (Wright et al. 2018).

   

  Congratulations to Dr. Balasubramanian, collaborators and her group of students for their accomplishments.

The Mayo Clinic

• Dr. Thomas Caulfield
  
  

  The Biomedical Sciences Program is pleased to highlight Dr. Thomas Caulfield’s Laboratory from the Mayo Clinic  

   

  Dr. Caulfield’s multidisciplinary  research revolves around biochemistry, biophysics, computer-aided modeling and in silico drug modeling. His research over the last several years has provided the basis for novel therapeutics for multiple diseases including cancer, neurodegenerative disease and metabolic diseases.  He has published over 55 peer-reviewed articles in high profile journals such as Brain, Nature Neurology Reviews, Neuron, Nature Human Genome Variation, Journal of Biological Chemistry, EMBO Reports etc.

   

  In a recent article, Caulfield and collaborators (Madamsetty et al. 2019) have used a combination of in silico, in vitro, and in vivo approaches, for Pancreatic ductal adenocarcinoma (PDAC) therapeutics. Using nanotechnology, the authors introduced drugs into poly (ethylene glycol)-functionalized nanodiamond (ND) particle. Aided by molecular simulations, the ND particle was simultaneously loaded with irinotecan and curcumin in ultra-small PEGylated NDs (ND-IRT + CUR). This approach was more efficacious in killing pancreatic cancer cells in culture than NDs with single drugs. The NDs were preferentially localized in tumors and metastatic lesions.  This study also showed that ND-IRT + CUR is capable of producing pronounced anti-tumor effects in two different clinically relevant, immune-competent genetic models of PDAC. Cytokine profiling indicated that NDs with or without drugs downregulated the expression of IL-10, a key modulator of the tumor microenvironment. These results open up novel opportunities for the treatment of pancreatic cancer.

   

  In a recent review, Caulfield and collaborators (Yamazaki 2019) discuss the targeting the apolipoprotein E (APOE) gene for late-onset Alzheimer disease  (AD) by precision medicine. Current evidence suggests that a major pathway by which APOE4 increases the risk of AD is by driving earlier and more abundant amyloid pathology in the brains of APOE*ε4 carriers. Numerous amyloid-β (Aβ)-dependent and Aβ-independent pathways are differentially modulated, by APOE isoforms. Accumulating evidence show that APOE influences tau pathology, tau-mediated neurodegeneration and microglial responses to AD-related pathologies. Further, APOE4 is either pathogenic or shows reduced efficiency in multiple brain homeostatic pathways, including lipid transport, synaptic integrity and plasticity, glucose metabolism and cerebrovascular function.

   

   In a further elegant study, Caulfield and collaborators (Caulfield et al. 2019) have investigated the frameshifting that occur in the ribosome during mRNA decoding. Using MacroMolecularBuilder (MMB) simulation, the authors suggest a novel, non-doublet decoding mechanism for −1 frameshifting by tRNA^Ser3 at Ala (GCA) codons. This study emphasizes the crucial role of molecular simulation in understanding basics in molecular biology.

   

  SPINOFFs

  Well known in the field of drug discovery and design, Dr. Caulfield has extensive experience in inventions, patents and spin off companies. He is a co-founder of a company via Mayo Ventures with approximately a 4% stake in the company (Series A filing valued at $23 M for the Parkin activator compounds for treatment of mitophagy-derived Parkinson’s Disease).  He is also involved in numerous other startup ventures.

   

  Patents:

   Compounds and Methods for Treating Cancer and Renal Carcinoma
  John A. Copland III Ph.D.; Han W. Tun M.D.; Thomas Caulfield Ph.D.; Christina Von Roemeling; Laura Ann Marlow 70391382 US 08/2015 02/2016

   Substituted Imidazo [4'] Cyclopenta [1,2-E) Pyrrolo[1,2-A] Pyrazines and Oxazolo[4,5] Cvclopenta[1,2-E) Pyrrolo[1,2-A] Pyrazines For Treating Brain Cancer. Han W. Tun M.D., Thomas Caulfield Ph.D., Takuma Kamon, Zhimin Li Ph.D., Yushi Qiu, Daisuke Shigeoka, Takehiko Yoshimitsu 9464093 USA 04/2015 10/2016

   Treating Brain Cancer Using Agelastatin A (AA) and Analogues Thereof
  Thomas Caulfield Ph.D., Takuma Kamon, Zhimin Li Ph.D., Yushi Qiu, Daisuke Shigeoka, Han W. Tun M.D., Takehiko Yoshimitsu 2906564 DE 10/2013 08/2018

   Small molecule activators of Parkin enzyme function. Springer, Wolfdieter, Ph.D.; Fiesel,  Fabienne C., Ph.D.; CAULFIELD, Thomas R., Ph.D. 0169158 USA 07/2017 06/2019

   

  Current Research Grants

   

  Co-Investigator: Early-Onset Parkinson's Disease Is a Mitochondrial Disease: A Nigral Mitochondrial Cytopathy (Initiating PI on Partnering PI PR160606 PRMRP 2016). Funded by Department of Defense.

  (W81XWH-17-1-0248) 08/2017 - 08/2020

   

  Co-Investigator: High-throughput Screen for Discovery of Ciliary Neurotrophic Factor (CNTF) Receptor Agonists for the Treatment of Amyotrophic Lateral Sclerosis (ALS). Funded by National Institutes of Health. (NS110960)

  05/2019 - 04/2022

  Co-Investigator. Molecular mechanisms of PINK1-PRKN directed mitochondrial quality control (NS085070 Renewal). Funded by National Institute of Neurological Disorders and Stroke. (RF1 NS085070)

  09/2019 - 05/2024

   

  Federal sub award

  Program Director /Principal Investigator:

  Variant Hemoglobin and Cardiorespiratory Regulation in Humans (PS on Joyner R35 at MCR). Funded by National Heart, Lung, and Blood Institute. (HL139854)

  01/2018 - 11/2024

   

  Mayo Clinic

  Co-Investigator: Discovering a specific TRPV2 agonist to treat Polycystic Kidney Disease. Funded by CCaTS-CBD Pilot Awards for Team Science

  01/2020 - 12/2020

   

  Congratulations to Dr. Caulfield, collaborators and his group for their accomplishments.

   

   

• Dr. Sunil Krishnan

  The Biomedical Sciences Program is pleased to highlight Dr. Sunil Krishnan’s Laboratory from the Mayo Clinic

  Sunil Krishnan MBBS, M.D., is a radiation oncologist specializing in the treatment of gastrointestinal cancers. His clinical and basic research focus areas include:

  • Management of esophagogastric, hepatobiliary, pancreatic, and anorectal tumors with radiation therapy
  •  Stereotactic body radiation therapy, proton radiation, intraoperative radiation, and brachytherapy.
  • Coordination of multidisciplinary care across departments including medical oncology, surgical oncology, and interventional radiology.
  • Identifying personalized strategies to maximize the efficacy of treatment while minimizing adverse effects of treatment.

  Dr. Krishnan is active in patient-centered research via clinical trials. His laboratory research is focusing on identification of compounds and nanoparticles that sensitize tumors to radiation therapy. His laboratory is also involved in translational research aimed at defining biomarkers of response to treatment.

   Dr. Krishnan was selected by The American Society for Radiation Oncology (ASTRO) in 2019 to receive the ASTRO Fellow (FASTRO) designation. The ASTRO Fellows program recognizes individuals who have made significant contributions to the field of radiation oncology and to the Society through research, education, patient care and service to the field.

   

  He has published over 190 peer-reviewed articles in high profile journals such as Am J Clin Oncol, Blood, BMC Cancer, Cancer Res, cancer, Clinical Cancer Research, J Clin Oncol, J Natl Cancer Inst, Int J Nanomedicine, Nanoscale, Nanomedicine, Oncotargets, PLoS One, Radiother Oncol, Scientific Reports etc.

   

  In a recent article Krishnan and collaborators (Habiba et al, 2019) showed that the radiation Therapy efficacy could be enhanced using Silver Nanoprisms decorated with PEGylated graphene quantum dots (pGAgNPs) as radiosentitizers. These Nanoprisms were taken up readily intracellularly. These Nanoparticles caused radiosensitization in radiation-sensitive HCT116 and relatively radiation-resistant HT29 colorectal cancer cells. Treatment with nanoparticles and a single radiation dose of 10 Gy significantly reduced the growth of colorectal tumors and increased the survival time as compared to treatment with radiation only. These findings open up novel opportunities for enhancing colorectal cancer radiation therapy efficacy using the nanoparticles.

   

  In a current review, Krishnan’s group (Li et al. 2019) discussed the present and future status of nanoparticle-enhanced cancer immunotherapy strategies. This comprehensive review addresses intensified delivery of tumor vaccines and immune adjuvants, immune checkpoint inhibitor vehicles, targeting capacity to tumor-draining lymph nodes and immune cells, triggered releasing and regulating specific tumor microenvironments, and adoptive cell therapy enhancement effects. Combining nanotechnology with immunotherapy offers considerable promise in addressing side effects and enhanced tumor tissue accumulation.

   

  Further, Krishnan and collaborators (Royam et al. 2019) performed a meta-analysis of miRNAs as predictors of chemotherapeutic response in pancreatic cancers. The research was based on articles collected from a thorough search of PubMed and Science Direct databases for publications spanning from January 2008 to December 2018. A total of 48 miRNAs have been studied, and 18 were observed to have possible contributions to chemoresistance, while 15 were observed to have possible contributions to chemosensitivity. 41 drug-related genetic pathways have been identified, through which the highlighted miRNA may be affecting chemosensitivity/resistance. The results implicate multiple miRNAs that have possible associations with modulation of chemotherapy response in pancreatic cancer patients. This comprehensive meta-analysis opens up new opportunities to discover novel biomarkers for response to chemotherapeutic interventions in pancreatic cancer.

   

  Active Grants

  R01DE028105   (Krishnan, Skinner)                                                                 12/27/2018-12/31/2023

  NIDCR/NIH

  Enhancing immune mediated head and neck cancer anti-tumor activity using nanoparticles

  Major goals: To evaluate strategies to target radioresistance mediated by PD-L1 using targeted nanoparticles, enhancement of PDL1 expression, and interrogation of exhaustion mechanisms.

   

  U01CA216468   (Lin, Krishnan)                                                                          09/05/2017 – 08/31/2022

  NCI/NIH

  Enhancing Chemoradiation Efficacy through Unbiased Drug Discovery Approaches

  Major goals: Screen the entire CTEP portfolio of drugs for radiosensitization potential in lung and pancreatic cancer models and evaluate the effect of tumor heterogeneity

   

  R44CA199058 (Saraf)                                                                                           08/01/2018 – 04/30/2020

  NIH/NCI

  A prognostic blood test to monitor pancreatic cancer treatment by miRNA profiling

  Major goals: To identify circulating miRNA markers of treatment response in pancreatic cancer

  Role: Co-investigator

   

  75N91019C00016    (Papineni)                                                                           09/16/2019 - 06/15/2020

  NCI/NIH

  A versatile radiation-triggered phosphor platform for localized anti-cancer therapy

  Major goals: To develop nanoscintillators that are triggered by radiation for x-ray induced photodynamic therapy of pancreatic cancer

  Role: Academic PI of SBIR contract

   

  75N91019C00043   (Papineni)                                                                           9/16/2019 - 9/15/2021

  I-PARTS Integrated Platform for Anti-Cancer Radiation Therapeutic Screening

  Major goals: To develop a high throughput system

  Role: Academic PI of SBIR contract

  Patents

  Radiation therapy with orthovoltage X-ray minibeams

  10,124,194

  Radiation therapy with segmented beams of protons and other ions

  10,124,194

  Use of nanoparticles in the photodynamic treatment of tumors and non-destructive testing

  9,550,071

  Treatments of disease or disorders using nanoparticles for focused hyperthermia to increase therapy efficacy

  9,211,419

  Use of nanoparticles in the photodynamic treatment of tumors

  8,328,785

   

  Congratulations to Dr. Krishnan, collaborators and his group for their accomplishments.

   

   

   

• Dr. Evette Radisky

  The Biomedical Sciences Program is pleased to highlight Dr. Evette Radisky’s Laboratory from the Mayo Clinic

  Dr. Radisky is a Professor of Cancer Biology at the Mayo Clinic College of Medicine and Science and Associate Dean for Mayo Clinic Graduate School of Biomedical Sciences. She is also on the External Advisory Board to the UNF Biomedical Sciences Program. Dr. Radisky is on the Editorial Board of the Journal of Biological Chemistry, and has served on the Meetings and Publications Committees of the American Society for Biochemistry and Molecular Biology (ASBMB). She has served as an ad hoc reviewer for numerous peer-reviewed journals and on study sections of the NIH and Department of Defense.

   

  Dr. Radisky’s research has been funded by agencies including the Department of Defense, National Cancer Institute, US-Israel Binational Science Foundation. She has published over sixty peer-reviewed publications in high impact journals including Biochem J, Cancer Cell, J Biol Chem, Cancer Res, Nat Commun, Nat Cell Biol, Oncotarget, PLoS One, Proc Natl Acad Sci U S A., Scientific Reports and Sci Transl Med.

   

  Dr. Radisky’s research revolves around proteases, their role in cancer progression and metastasis, molecular recognition between proteases and inhibitors, and development of protease inhibitors as novel cancer therapeutics.

   

  Serine proteases are implicated as key drivers and facilitators of lung cancer malignancy. However, the complex networks in which these enzymes function have complicated the pursuit of these proteases as therapeutic targets. In a recent article, Dr. Radisky’s group (Ma et al. 2019) implicated a signaling pathway consisting of PRSS3/mesotrypsin and kallikrein-related peptidase 5 (KLK5) in lung adenocarcinoma.

  The study showed that elevated PRSS3/mesotrypsin expression is a prognostic indicator for poor outcome for patients with lung adenocarcinoma. They further demonstrated that targeting of PRSS3/mesotrypsin reduces lung adenocarcinoma cell invasiveness and proliferation.  Using transcriptional profiling it was shown that PRSS3/mesotrypsin and KLK5 control a common malignancy-promoting pathway. These experiments implicate PRSS3/mesotrypsin-KLK5 signaling pathways in lung adenocarcinoma, opening up novel opportunities for selectively targeting these pathways for drug development.

   

  Targeting protein-protein interactions is highly attractive strategy for selective pharmaceutical development. However, such interactions involve often involve large families of related proteins and offer a challenge for selective drug development. In an article, Radisky and collaborators (Naftaly et al. 2018) describe an approach to identify a new generation of targets based on selective protein-protein interactions.

  They have used a combination of multi-target selective library screening and in silico next-generation sequencing analysis. Initially, a map of the binding landscape of a non-selective trypsin inhibitor, the amyloid protein precursor inhibitor (APPI), to each of the four human serine proteases (kallikrein-6, mesotrypsin, and anionic and cationic trypsins) was established. This map was then used to dissect and improve the affinity and selectivity of APPI variants toward each of the four proteases. This novel approach provides a framework for the development of a new generation of target-selective probes. Based on selective protein-protein interactions, novel therapeutic agents will likely emerge from these research endeavors.

   

  The molecular and biochemical approaches that are undertaken in Dr. Radisky’s laboratory provide a framework for discovery of novel druggable targets and highly selective molecularly targeted agents for cancer therapy.

   

  Congratulations to Dr. Radisky, collaborators and her group for their accomplishments.

• Dr. Joy E.V. Wolfram

  Nanomedicine and Extracellular Vesicles Laboratory

  The Biomedical Sciences Program is pleased to highlight Dr. Joy Wolfram’s Laboratory from the Mayo Clinic

  
  

  Dr. Wolfram, a leader in the emerging field of nanomedicine, is an Amgen Scholar and has made the Forbes annual 30-under-30 list for 2019. Her research has been cited in numerous national and international press.

   

  Dr. Wolfram is a research faculty at the Department of Biology, College of Arts & Sciences at UNF. Dr. Wolfram’s research interests revolve around extracellular vesicle therapeutics, nanomedicine and organotropic drug delivery for diverse diseases including cancer and inflammation.

   

  In a recent review (Wolfram and Ferrari, 2019), Dr. Wolfram discusses the current state-of-the-art in nanotherapeutics with particular emphasis on clinically approved cancer nanodrugs as well as potential candidates in the pipeline. Nanoparticles possess unique biological and physical properties that make them ideal for targeted delivery. A multitude of conventional chemotherapeutics and macromolecules such as proteins can be incorporated into the nanoparticles. Drugs and bioactive molecules encapsulated into nanoparticles escape immunosurveillance and normal degradation mechanisms, thus making the approach more effective than conventional drug delivery.

   

  Biodistribution and clearance is a limiting factor for pharmaceuticals and biomolecules that affects efficacy and side effects. Drugs are rapidly cleared from circulation and distribute throughout the body resulting in reduced efficacy and adverse side effects. Further limitations of nanoparticles include immune clearance and impaired diffusion in the tissue microenvironment. In another review article (Busatto et al. 2019a), Dr. Wolfram and collaborators discuss the organotropic drug delivery using synthetic nanoparticle and extracellular vesicle delivery strategies.  Extracellular vesicles are cell-secreted nanoparticles with endogenous site-specific targeting properties. A major limitation for the use of extracellular vesicles as delivery vehicles for therapeutic agents is inefficient methods of isolation from biological sources. In a recent study (Busatto et al. 2019b), Dr. Wolfram’s laboratory describes a method for obtaining extracellular vesicles from human cells and tissues in an efficient and scalable manner, opening up future opportunities for clinical translation.

   

   

  Site-specific localization of drugs can reduce toxicity and improve efficacy. Nanoparticles offer a promising potential to achieve this. A major barrier to this approach is that, a vast amount of the systemically injected nanocarriers accumulated in the liver and spleen due to resident macrophages that form the mononuclear phagocyte system. In a recent elegant study, Dr. Wolfram and collaborators (Wolfram et al. 2017) used antimalarial agent chloroquine and showed that it reduced the uptake of nanoparticles in macrophages by suppressing endocytosis. In preclinical models, treatment with chloroquine significantly decreased the accumulation of liposomes and silicon particles in the mononuclear phagocyte system. This resulted in improved delivery to the tumor in an organ-specific manner. These studies show that chloroquine as a macrophage-preconditioning agent can help address the major barrier in nanomedicine. This study opens up novel opportunities for the combined use of macrophage-modulating agents with nanomedicine to improve site-specific delivery.

  Congratulations to Dr. Wolfram, her collaborators and students for their accomplishments.