2016 Grant Recipients
Sui Wang, PhD
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Stanford University, Stanford, CA
Dissection of Gene Regulatory Networks Underlying Diabetic Retinopathy
Diabetes affects the retina, the inner layer of the eye responsible for communicating the images we see to the brain. Diabetic retinopathy is one of the most common complications of diabetes and is the leading cause of blindness among working-age adults. Currently, the only therapies for retinopathy are laser treatment and injection of drugs, which are used to slow down the progression of retinopathy, but are not able to reverse vision loss. To instead prevent diabetic retinopathy before it starts, researchers need to better understand how it develops in the first place. Dr. Wang is pursuing an innovative approach to understanding how diabetes impacts gene activity in the retina. She plans to map the gene networks involved in the initial development and progression of retinopathy. With this information, we can better identify early signs of retinopathy to begin treatment before vision loss occurs, and perhaps discover previously unknown molecules that may be candidates for the development of new drugs to preserve vision.
Phillip James White, PhD
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Duke Molecular Physiology Institute, Duke University, Durham, NC
A New Homeostatic Mechanism for Metabolic Control
Very frequently, fatty liver and insulin resistance precede the onset of type 2 diabetes. Compounds called "branched chain amino acids" (BCAAs), which come from certain proteins in our diets, are linked to insulin resistance and risk for developing type 2 diabetes. However, precisely how circulating BCAAs are connected to abnormal glucose and lipid metabolism is unclear. Dr. White has discovered that some of the components of the molecular network that go awry in protein metabolism and prevent BCAAs from breaking down also interact with both glucose and lipid metabolism pathways in the liver. Dr. White's project will examine this network and how it is controlled. He hopes to further define how the molecules interact to control fat and glucose metabolism – and then to identify where new drug development efforts may be focused to treat prediabetes, fatty liver disease and type 2 diabetes.
Daniel J. Ceradini, MD, FACS
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Wyss Department of Plastic Surgery, New York University Langone Medical Center, New York, NY
Therapeutically Targeting Keap1/Nrf2 Dysfunciton in Diabetes
Diabetes is the leading cause of non-healing wounds and lower extremity amputation in the U.S. Despite efforts to tightly control blood glucose in people with diabetes, poor wound healing persists as a common complication. Dr. Ceradini has discovered that high blood glucose levels associated with diabetes disrupt antioxidant networks important for tissue regeneration. His project seeks to determine whether restoring this critical antioxidant pathway to normal will reverse the impaired tissue regeneration caused by diabetes. Using innovative approaches and technologies, Dr. Ceradini will develop and test a novel therapy to restore the antioxidant protection program and determine whether it can overcome poor wound healing in diabetes.
Zachary A. Knight, PhD
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University of California, San Francisco
Reinvestigation of the Arcuate Feeding Circuit
Because the brain controls food intake, it is likely to be an important target for new therapeutics to reduce obesity. However, little is known about the specific site in the brain where environmental or dietary signals override the system that normally regulates feeding and weight maintenance. Dr. Knight's project will use new technologies to investigate the key neurons in the brain that control food intake. If successful, this project will identify the signals that are responsible for activating the sensation of hunger, determine how the neurons motivate food consumption, and clarify how obesity leads to dysregulation of these neurons. Understanding of these networks in the brain may lead to development of new therapies to treat or prevent obesity by stimulating or inhibiting the neurons responsible for hunger and feeding behavior.
Praveen Sethupathy, PhD
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Systems Approach to Defining Genetic Regulation of Intestinal Physiology and Gut Microbiota in Diet-Induced Obesity
In the human body, microorganisms outnumber human cells ten to one. These microorganisms, mostly bacteria, are influenced by both diet and genetic factors and are linked to metabolic disease. The gastrointestinal tract is home to a significant population of microorganisms and is the primary organ system responsible for absorbing nutrients from food. Obesity and diabetes are associated with changes in the microbial communities of the gut and with impaired intestinal function. Dr. Sethupathy's project seeks to identify the genetic factors that contribute the most to shaping the way our intestines respond to gut microorganisms under normal conditions and in diet-induced obesity and diabetes. These studies could lead to the identification of new therapeutic targets that may be leveraged to prevent or effectively treat obesity and diabetes.
Andrew Scharenberg, MD*
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Seattle Children's Hospital and Seattle Children's Research Institute, Seattle, WA
Regulatory T-Cell Stabilization via Gene Editing as Novel Therapy for Type 1 Diabetes
Development of type 1 diabetes is known to involve the immune system inappropriately attacking the body's own insulin-producing beta cells. Several lines of evidence suggest that dysfunction of a type of immune cell, known as a thymic regulatory T-cell (tTreg), leads to a breakdown of normal protection from the immune system in insulin-producing beta cells. When the tTreg cells fail, the immune system begins to attack and destroy the body's own beta cells, leading to type 1 diabetes. Dr. Scharenberg is applying an innovative approach that he developed for "editing" genes to try to tackle type 1 diabetes. Using this technology, his Pathway to Stop Diabetes project aims to edit genes in tTreg cells to preserve their function and protect the beta cells from autoimmune attack, potentially preventing or reversing type 1 diabetes.
* Dr. Scharenberg relinquished his Pathway award in 2017 to accept an opportunity to become Chief Scientific Officer at Casebia Therapeutics. He credits the Pathway Visionary Award with developing the scientific expertise he needed to translate cell and gene therapies to type 1 diabetes. He continues to aim to apply these novel approaches to the treatment of autoimmune diseases, including type 1 diabetes.