Privalsky, Martin L., PhD
Protection against glucose intolerance conferred by alternative corepressor splicing.
General Research Subject: Type 2 Diabetes
Focus: Adipocytes, Gene Chips and Microarrays, Integrated Physiology, Integrated Physiology\Insulin Resistance
Type of Grant: Basic Science
Project Start Date: July 1, 2012
Project End Date: June 30, 2015
The body's ability to utilize sugars and fats is regulated by an interacting network of proteins, referred to as transcription factors that help control the expression of key genes involved in metabolism. These transcription factors exert their actions by partnering with accessory proteins, referred to as corepressors and coactivators. Consumption of excess calories leads to changes in these regulatory networks that allow these calories to be properly stored for future use. Misregulation of this regulatory network can lead to type-2 diabetes.
My laboratory has recently discovered that different corepressors are created in a process called alternative splicing, by which different pieces of a master corepressor template are assembled together to create a series of different "variants." Different corepressor variants are expressed in different cells, partner with different transcription factors, and regulate different genes. Significantly, we have observed that a change in corepressor splicing during normal fat cell formation allows the fat cell to absorb extra calories safely while protecting against the glucose intolerance/type-2 diabetes typical of many forms of obesity.
This proposal seeks to understand how this corepressor splicing process works to protect the healthy individual against disease, and what goes wrong in type 2 diabetes patients that overwhelms this protection. This information will help us understand what causes diabetes, and will aid in designing future drugs that, by targeting specific corepressor splice variants, can create the protective outcomes we observe in our genetic studies while minimizing the undesired side effects of the drugs in current use.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
We are investigating how the healthy body responds to excess calories so as to store them safely, and what goes wrong in type 2 diabetes that results in this healthy process becoming distorted and leading to metabolic disease.
Our ADA project seeks to understand how fat cells form and how they regulate their metabolism under different nutritional conditions. My laboratory has discovered a previously unrecognized mechanism by which this occurs that involves regulatory proteins called corepressors. Corepressors help program how cells function, and we have shown that a process, referred to as alternative mRNA splicing, alters corepressors to reprogram the metabolism of fat cells as they develop and function in the body.
By further studying this process, we hope to better understand how to maintain the correct metabolism in these fat cells and prevent obesity leading to type 2 diabetes. Our research will also provide new insights into ways of improving the drugs used in type 2 diabetes so as to enhance their effectiveness and minimize their undesirable side-effects.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Our project will lead to a better understanding of ways to reduce the risk that gain of weight will cause type 2 diabetes in otherwise healthy individuals. Our project will also aid in the design of new drugs that can better and more specifically treat type 2 diabetes while minimizing the side effects that often limit the use of current versions of these pharmaceuticals
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
Certainly a major reason for me, personally, to become involved in diabetes research is the impact this disease has had on the people I know and I care for. Both type I and type II diabetes have affected people in my circle of friends, relatives, and acquaintances, and I am well aware of the effects of these diseases on peoples' lives.
My research had been previously focused on exploring basic aspects of endocrinology; when it become clear that my laboratory's latest results had significance for understanding normal metabolism and the defects that lead to type 2 diabetes, I was thrilled that I might have the opportunity, through my own research, to better understand this disease and to help discover improved ways of preventing and treating it. This ADA award is very exciting to me because it will allow me to make full use of that opportunity. By permitting me to pursue this new direction in my research, I will be able to feel that I am contributing to the solution of a major health problem that affects not just the United States, but the world as a whole.
In what direction do you see the future of diabetes research going?
I hesitate to offer my opinion, which is far from expert, on such a broad topic. From my limited perspective as a researcher, however, I believe that the amazing breakthroughs that have occurred (and continue to occur) in molecular and cellular biology will increasingly reveal the causes of diabetes, and provide more and more resources that will aid in its prevention and treatment. I think one important component of this progress will be further discoveries of how specific components of diet can protect against, or increase the risk of, type 2 diabetes. I also think that genetic factors will continue to be discovered that will help guide individuals as to the best ways of protecting their own health. And I think that the panel of drugs that is used to treat diabetes will become increasingly sophisticated, with additional novel compounds being discovered that will help more people while producing fewer negative effects.
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