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The University of Florida Department of Pathology, Immunology and Laboratory Medicine Experimental Pathology Division was awarded several new research grants starting in 2017. (references Experimental Pathology Researchers Mark A. Atkinson, Ph.D., Timothy Garrett, Ph.D., Clayton E. Mathews, Ph.D., David A. Ostrov, Ph.D. and Wen-I Yeh, Ph.D., as well as UF Biochemistry Undergraduate Student Caridad Infante)

Published: March 10th, 2017

Category: Department News

Members of our Experimental Pathology Division were recently awarded a number of research grants. Read more about these promising research opportunities below:

Study title

Direct sponsor name

Flow-through sponsor name

Activated award date

Overall end date

Integrated Program for Human Pancreas Procurement and Analysis

Primary investigator:
Mark A. Atkinson, Ph.D.

Vanderbilt University Medical Center National Institute of Diabetes and Digestive and Kidney Diseases February 9, 2017 June 30, 2019
The National Institute of Diabetes and Digestive and Kidney Diseases has awarded a grant for this three-year study to University of Florida Primary Investigator, Mark A. Atkinson, Ph.D., and Primary Investigator Alvin C. Powers, M.D., at Vanderbilt University. The $3.6 million UF portion of the grant will enable Dr. Atkinson and his team to work closely with investigators at Vanderbilt University and University of Pennsylvania, which were both also granted separate awards, to advance strategies for the prevention and/or reversal of type 1 diabetes.

Dr. Atkinson’s goal is to strengthen and expand current donor procurement outreach and screening for pre-diabetes organ donors for human type 1 diabetes research, established by generous support from the Juvenile Diabetes Research Foundation (JDRF) and the Leona M. and Harry B. Helmsley Charitable Trust. The precious and hard-to-find donor samples will be shared with the partnering universities to address the human type 1 diabetes etiopathology for finding a cure.

Network for Pancreatic Organ Donors with Diabetes (nPOD) Annual Meeting Costs – 2017 – 18

Primary investigator:
Mark A. Atkinson, Ph.D.

Juvenile Diabetes Research Foundation (JDRF) N/A February 2, 2017 December 31, 2017

Human Atlas of the Neonatal Development and Early Life Pancreas (HANDEL-P)

Primary investigator:
Mark A. Atkinson, Ph.D.

Leona M. and Harry B. Helmsley Charitable Trust N/A February 8. 2017 January 31, 2020
Professor Mark A. Atkinson, Ph.D., was recently awarded a grant from the Leona M. and Harry B. Helmsley Charitable Trust for a three-year study on early human pancreas development. The goal of this project is to procure and study pancreata in early the early stages of human life, especially during the period from birth through adolescence. One predominant question Dr. Atkinson hopes to address is, “What early event, either beta cell or immune based, initiates this autoreactive response that results in type 1 diabetes?”

The $3.3 million award will facilitate collaborations among investigators from the University of Florida, Vanderbilt University, Stanford University and Allegheny-Singer Research Institute to uncover early human pancreas development and move medicine toward better human type 1 diabetes prevention techniques and/or a cure for the illness.

Causes and Consequences of Acid pH in Tumors

Primary investigator:
Timothy Garrett, Ph.D.

H. Lee Moffitt Cancer Center & Research Institute National Cancer Institute, National Institutes of Health February 2, 2017 August 31, 2017
The extracellular pH of tumors is unequivocally acidic. Importantly, tumor acidity can be selectively neutralized with oral buffers, which has been shown to inhibit metastasis and tumor progression and combine with anti-tumor immune therapies. To thrive in an acidic environment, tumor cells must adapt to growth under acidic conditions, under a parent grant awarded to Robert J. Gillies, Ph.D., of Moffitt, Cancer Center, we have also observed that acid adaptation involves chronic autophagy, as well as redistribution of lysosomes to the plasma membrane. During the course of this work, we also noted that growth in acidic conditions leads to dramatic increases in cytoplasmic lipid droplets. Increased lipogenesis is frequently observed in cancer, which are stored in cytoplasmic droplets (i.e., adiposomes) that are dynamic, as well as organelles with cores of cholesterol esters and triacylglycerides surrounded by a shell composed of polar lipids and proteins (i.e., perilipins).

It is believed that adiposomes function as crucial metabolic hubs by playing central roles in energy and membrane metabolism and production of signaling molecules.  Although their biogenesis is well-studied in liver and adipocytes, it is unknown why this phenotype is prevalent in cance, or how and why they are induced by acidic conditions. We have shown that low pH induces lipid droplet accumulation with concomitant increases in fatty acid synthesis and beta-oxidation pathways in breast cancer cells. Inhibition of either the anabolic or the catabolic pathways was significantly toxic to cells under acidic, compared to neutral, culture conditions. We therefore hypothesized in this metabolomic supplement proposal that the lipogenic phenotype is a necessary adaptation for survival in acidic niches; and that inhibiting this could provide therapeutic benefits. We will perform shotgun lipidomic profiling using LC-MS/MS of lipid droplets isolated from acid-treated and acid-naïve cells. These will be correlated to focused gene expression profiles to assess lipid metabolic pathways, as well as adiposome-associated proteins, such as those of the perilipin family, which are involved in intracellular signaling pathways.

Serum Protein Biomarkers for Predicting Type 1 Diabetes Development

Primary investigator:
Clayton E. Mathews, Ph.D.

Pacific Northwest National Laboratory National Institute of Diabetes and Digestive and Kidney Diseases January 18, 2017 June 30, 2019

Testing Skin Sensitizers for Binding to Human Leukocyte Antigen (HLA)

Primary investigator:
David A. Ostrov, Ph.D.

 

UT–Battelle U.S. Department of Energy February 16, 2017 September 29, 2017
Allergic contact dermatitis is a delayed-type hypersensitivity (type IV) reaction that develops following an encounter with various kinds of chemicals, including fragrances. The evaluation of sensitization potential of cosmetic ingredients and formulations is of paramount importance for hazard and risk assessments. There is a considerable interest in reducing and ultimately replacing animal testing with in-vitro assays. Reliable in-vitro tests should be based on the mechanism(s) by which chemicals induce sensitization. The project aims to develop in-silico, biochemical and in-vitro cellular assays to detect human leukocyte antigen (HLA) binding.

Impacts of Co-stimulation Molecules CD226 and TIGIT on Natural Killer Cell Immunoregulation and Function During Type 1 Diabetes

Primary investigators:
Wen-I Yeh, Ph.D.
and Caridad Infante

American Diabetes Association N/A February 9, 2017 December 31, 2017
There are multiple evidence-indicating viral infections that may be important in the initiation of type 1 diabetes, where natural killer (NK) cells are critical during viral eradication. Primary Investigator Wen-I Yeh, Ph.D. and UF Biochemistry Undergraduate Student Caridad Infante hypothesize that there is a functional imbalance in the ratios of these co-stimulatory molecules in type 1 diabetes, favoring the overexpression of CD226 over TIGIT and resulting in pathogenic NK cell activity. In examining the expression of these receptors, they discovered an elevated activating receptor CD226 on NK cells in type 1 diabetes cohort and no difference for TIGIT compared to healthy controls.They will investigate if genetic variation of CD226 influences NK cell function. While gaining a better understanding of how T1D occurs, their studies may provide key insights into therapeutic intervention in disease prevention and progression.

Dr. Yeh is a postdoctoral associate who works with Todd M. Brusko, Ph.D. She focuses on how type 1 diabetes-associated genes (CD226 and TIGIT) shape dysfunctional immune responses in the pursuit of a cure.

Caridad Infante works with Dr. Yeh in examining the roles of inhibitory and activating receptors, TIGIT and CD226 respectively, in natural killer cells. Infante’s dedication to research resulted in her being awarded an Undergraduate Minority Internship Award in early 2017 from the American Diabetes Association.