Graff, Jonathan M., MD, PhD
Characterization of novel genetic factors of hyperglycemia identified in Drosophila melanogaster through a partial genome screen
General Research Subject: Type 2 Diabetes
Focus: Genetics, Genetics\Type 2 Diabetes, Insulin Action\Glucose Transport, Integrated Physiology, Integrated Physiology\Muscle
Type of Grant: Mentor Based Postdoctoral Fellowship
Project Start Date: July 1, 2012
Project End Date: June 30, 2016
The diabetes epidemic is growing at an alarming rate worldwide. Currently, 6% of adults between the ages of 20 to 69 are estimated to suffer from type 2 diabetes. Over time, diabetes can give rise to numerous complications including impaired vision, kidney failure, nerve damage, and heart disease. Obesity is considered a major risk factor for developing diabetes; however, diabetes is a partially heritable disease. A child's probability of acquiring diabetes over his or her lifetime significantly increases if both parents are diabetic. Several genetic variations predisposing individuals to diabetes have been identified; however, there still remains a large gap in our knowledge.
In an effort to narrow this gap, we conducted preliminary screening in our model organism, the fruit fly, to identify novel genetic defects that lead to chronic elevations in blood glucose levels. The major focus of this proposal is to verify the involvement of these new genes, not previously implicated in the regulation of blood glucose, in the pathogenesis of diabetes. Further, we will also examine the interaction of these genes with other genetic factors known to be vital in the maintenance of normal circulating glucose levels. The proposed experiments, which will be implemented in fly and mouse systems, seek to enhance our understanding of the underlying genetic causes of diabetes. We expect that promising data from this project will help accelerate diabetes research and may eventually present new drug targets for the control and treatment of type 2 diabetes.
Mentor: Jonathan M. Graff, MD, PhD Postdoctoral Fellow: Rupali Ugrankar, PhD
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
This project is geared toward identifying the various proteins that regulate blood glucose levels. Insulin is a well-known example, and one that has helped significantly in diabetes treatments. Our preliminary studies indicate there are dozens and dozens of additional molecules that regulate glucose homeostasis. The notion behind identifying proteins, in addition to insulin, that are important in regulating glucose levels is that such discoveries open new windows into prevention, treatments, or cures for diabetes.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
This project will help us understand how blood sugar is controlled. Such a step is essential to finding new methods to prevent, treat, or cure diabetes or its complications.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
My professional (and personal) mission is to discover and translate innovative science into breakthrough medicines for Diabetes. When I was a child one of my closest cousins developed Type I DM, I helped with insulin injections. I have spent essentially my entire professional career working towards eliminating this disease. For example during my M.D. Ph.D., I studied with Dr. Perry Blackshear, a prominent Diabetologist who, among other important advances, invented the implantable pump. I then honed my clinical Diabetes skills at the Massachusetts General Hospital training first in Internal Medicine and then Endocrinology/Metabolism. Of note, my wife (we both attended a meeting, organized by Ron Kahn and the Joslin Clinic during the mid 1980’s, for Medical Students focused upon a career in Diabetes, setting the stage for our relationship) is also a Massachusetts General Hospital-trained Internist and Endocrinologist with a passion for caring for folks with Diabetes.
During the next stage of my career, I studied with Dr. Douglas Melton, a pioneer in beta cell replacement/regeneration. Together, my training allowed me to attempt to make basic discoveries and translating them to the clinic. Indeed after joining the faculty, I founded Reata Pharmaceuticals based upon one of our basic discoveries. Reata’s lead program is a novel treatment for kidney disease due to Diabetes. Remarkably the medicine is already in the midst of the definitive Phase 3 clinical trial required for FDA approval, after a very successful Phase 2 trial as reported in the New England Journal of Medicine. This award will allow us to continue basic discovery with the hope of finding new Diabetes drugs.
In what direction do you see the future of diabetes research going?
I think that the future holds a vast number of important advances for Diabetes. Many of these improvements will hinge upon a better understanding of the underlying mechanisms of blood glucose control. Once the forces and molecules that regulate blood sugar are characterized, they will provide therapeutic targets that can be moved to the clinic.
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