Lazar, Mitchell A., MD, PhD
Epigenetic regulation of metabolism
General Research Subject: Type 2 Diabetes
Focus: Integrated Physiology\Insulin Resistance, Obesity\Animal Models
Type of Grant: Mentor Based Postdoctoral Fellowship
Project Start Date: July 1, 2009
Project End Date: June 30, 2013
Type 2 diabetes is complex disease. Genes are recognized to play a role, yet the frightening epidemic type 2 diabetes has emerged too rapidly to be explained by inherited mutations in the human genome. Much more culpable are the changes in diet and lifestyle that have paralleled the diabetes epidemic. Nevertheless, gene function clearly changes in diabetes. Rather than genetic change, we hypothesize that epigenetic change is responsible for these changes in gene function. Epigenetics is the term used to describe how gene expression is altered by environmental factors without changes in genes. The most well-documented epigenetic mechanism involves changes in how gene are packaged in cells. Our studies will specifically perturb one important epigenetic regulator, an enzyme called histone deacetylase 3 (HDAC3). We will determine how this alters the role of diet in inducing diabetes in mouse models, and which metabolic tissues (such as liver, muscle, and fat) are most affected. Since HDAC3 is an enzyme, its activity may be modulated by small molecules that inhibit or potentiate its activity. Such small molecules could be turned into new drugs that will ameliorate the development and course of diet-induced diabetes.
Mentor: Mitchell Lazar, MD, PhD Postdoctoral Fellow: Seo-Hee You, PhD
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
Diabetes runs in families and is clearly related to genetics, yet wholescale changes in the genome of our population cannot account for the frightening pace at which diabetes is increasing in our society. Rather, it is the environment, interacting with our genes, that is likely to be responsible. The environment influences gene expression via epigenetic change. 'Epigenetics' refers to the study of how the expression of genes in the genome are controlled by modification of the DNA and/or of the nuclear structures that the DNA wraps around in the cell nucleus (nucleosomes). Nucleosomes are coposed of histone proteins that are modified by reversible incorporation of acetyl groups. Histone deacetylases (HDACs) take off the acetyl groups, and have been shown to regulate metabolism.
One HDAC in particular, called HDAC3, is critical for regulating the response to hormones and dietary nutrients. The enzyme activity of HDAC3 requires interactions with one of two molecules called NCoR and SMRT. We have previously shown that mice with a mutant NCoR that cannot interact with HDAC3 are protected from diet-induced obesity and diabetes. In the present project, we are testing the effect of a similar mutation in SMRT, on weight gain and glucose control. Since HDACs are enzymes, they can be drug targets for inhibitors. Non-specific HDAC inhibitors are already being used to treat cancer. We hypothesize that the mutant mice will be protected from diabetes, thus opening the door for the development of HDAC3-specific inhibitors to treat diabetes.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
We are testing the role of a histone deacetylase (HDACs) in metabolic control. Since HDACs are enzymes, they can be drug targets for inhibitors that could be used to treat diabetes. In addition, it is now recognized that diabetes is due to complex interactions between genes and the environment, and the effects of HDACs is to modify the structure of the genome DNA in the cell nucleus. Thus this work will also help us to better understand the mechanisms by which the environment impacts on diabetes risk and severity.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
As an endocrinologist, I see the ravages of diabetes in the Rodebaugh Clinical Diabetes Center at the University of Pennsylvania. I also see it first hand from my own mother and father-in-law, both of whom are type 2 diabetics. As a parent, I am frightened by the statistics indicating that 1 in 3 children born in this millennium will develop diabetes. As a scientist, I am motivated by the challenge to understand the complex interplay of molecules and tissues in regulating metabolism. This award will allow me to pursue more vigorously the manner in which the environment regulates gene expression and metabolism, which goes awry in diabetes.
In what direction do you see the future of diabetes research going?
I believe that future diabetes research will take advantage of insights gained from analysis of the human and other mammalian genomes. This will include not only the complete identification of diabetes risk genes, but the functional understanding of how these cause diabetes. This knowledge, in turn, will be used to develop more rational and personalized preventive and therapeutic strategies.
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