Leff, Todd , PhD
A diabetes-associated human PPAR-gamma mutation that alters DNA binding specificity
General Research Subject: Type 2 Diabetes
Focus: Signal Transduction (Non-Insulin Action)
Type of Grant: Basic Science
Project Start Date: January 1, 2010
Project End Date: December 31, 2013
In spite of years of research the molecular mechanisms that cause diabetes are not fully understood. One approach to studying disease mechanism is to identify simple genetic mutations that cause the disease by altering the activity of a single protein or enzyme. Examining the details of how the mutation alters the activity of the protein can provide insight into the disease process. This project is focused on such a mutation in the gene that encodes a protein called PPAR-gamma. PPAR-gamma plays a key role in regulating insulin sensitivity, and is the target of the insulin-sensitizing, anti-diabetic, thiazolidinedione drugs. PPAR-gamma is a transcription factor that functions to regulate the expression of genes involved in controlling insulin sensitivity and other important metabolic processes.
The PPAR-gamma mutation that will be studied here was recently discovered in a Canadian kindred, and causes diabetes and a fat tissue disorder called lipodystrophy. Previous studies suggest that this mutation alters the ability of PPAR-gamma regulate the expression of metabolically important genes. The goal of this study is to characterize this mutation, and determine which genes are inappropriately regulated by the mutant form of PPAR-gamma. This study will provide insights into the pathogenesis of insulin resistance, a critical but poorly understood factor in the development of type-2 diabetes. The knowledge gained from this project will advance the possibilities for screening, treatment and prevention of this extremely prevalent and deadly disease.
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 focused on a specific aspect of type-2 diabetes. In particular, my work aims to understand the function of a protein known to play a key role in both the development and the treatment of diabetes. This protein is called PPAR-gamma, and although we already know a great deal about what it does, we do not understand the details of how it carries out its important functions. We know that PPAR-gamma is important in diabetes because of two well-established pieces of information. First, the anti-diabetic thiazolidinedione drugs (Actos & Avandia) function by stimulating the activity of PPAR-gamma. Second, we know that mutations in the PPAR-gamma protein that reduce its activity, cause an inherited form of diabetes. In spite of this knowledge, there are large gaps in our understanding of exactly how the activation of PPAR-gamma by these drugs leads to improvements in diabetes. As important, this research may help us understand why activation of PPAR-gamma also has certain undesirable side-effects. This information could ultimately help in the discovery of new anti-diabetic drugs with fewer side effects and better anti-diabetic activity.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
The overall goal of our research is to understand the details of how the body regulates metabolism and to determine exactly what goes wrong with this regulatory system during the development of diabetes. So in some sense this work is of a fundamental, or basic, nature and will only effect diabetes treatment and prevention indirectly, possibly by suggesting novel strategies for discovery and development of better anti-diabetes drugs. Even though our work is not specifically directed toward therapeutics, it is important to point out that the major focus of the work is a protein that we know plays a key role in the treatment of type-2 diabetes. This protein, called PPAR-gamma, is activated by the anti-diabetic thiazolidinediones drugs (Actos & Avandia). If our work is successful we will have developed a better understanding of the details of how this protein functions to regulate metabolism. This may help us understand why activation of PPAR-gamma has certain undesirable side-effects, and ultimately help in the discovery of new drugs with fewer side effects and better anti-diabetic activity.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
My interest is diabetes research is two-fold. First, as a biomedical researcher I would like to do something to improve human health. Diabetes and related metabolic disorders represent such a huge human health problem in the US (and around the world) that advancements in our understanding the basic biology of metabolism could have a significant impact on the health of the population. This means that results from ADA funded studies, including this project, could positively affect the health of a large number of people. Second, as a scientist, I find several aspects of the basic biology of diabetes and metabolic regulation intensely interesting. One thing that I find particularly intriguing is the complex 'whole body' nature of diabetes. More than many other diseases, diabetes involves multiple organs & tissues and is strongly related to how different organs communicate with each other.
This aspect of the disease presents unique research challenges that I find particularly exciting. A second aspect of the basic biology of metabolism that fascinates me is the complex and poorly understood interaction between the physiological system that regulates metabolic balance, and specific aspects of the external environment; e.g. nutritional status, physical activity and exposure to environmental pollutants. These and other environmental factors are very likely to exert a strong influence on metabolism and therefore affect diabetes susceptibility or severity in certain populations.
In what direction do you see the future of diabetes research going?
I believe that in the next several years, major advancements will be made in our understanding of the causes of both type 1 and type 2 diabetes, and that these advancements will stimulate the development of new therapeutic strategies that will ultimately benefit those with diabetes. I also believe that an improved understanding of the basic mechanisms by which the body regulates metabolism will allow us to make specific recommendations regarding lifestyle (e.g. nutritional behavior) that could have a major impact on diabetes susceptibility. Finally, I think the emerging field of stem cell biology will have a large impact on both type 1 and type 2 diabetes treatments, although this may take many years of research to accomplish.
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