Shi, Hang , PhD
DNA methylation of macrophage PPARgamma1 promoter regulates obesity-induced inflammation and insulin resistance
General Research Subject: Insulin Resistance Pre Diabetes
Focus: Insulin Action\Insulin Resistance, Insulin Action\Transgenic Models, Integrated Physiology, Integrated Physiology\Insulin Resistance
Type of Grant: Basic Science
Project Start Date: July 1, 2013
Project End Date: June 30, 2016
Type 2 diabetes has reached epidemic proportions in the United States. Although the cause of diabetes remains to be a mystery, obesity appears to play a major role in the development of diabetes due to chronic inflammation from fat tissue. The fat-originated inflammation that occurs in obesity is associated with a switch from good anti-inflammatory macrophages (an immune cell) to bad inflammatory macrophages. It is not clear, however, why and how obesity tips the balance towards the increased content of bad macrophages in fat tissue that leads to the exaggerated inflammation. A cellular protein called peroxisome proliferator-activated receptor gamma (PPARgamma) regulates the balance between the bad and good macrophages in normal cellular process. While numerous studies have been devoted to the evaluation of genetic factors related to diabetes, much less is known about epigenetic regulation, a term used to describe how gene expression is regulated by environmental factors such as diets without alterations in the DNA sequence.
The central hypothesis of this proposal is that epigenetic regulation of PPARgamma in response to nutritional cues (eg saturated fat) causes the switch from good to bad macrophages, leading to obesity-induced inflammation and diabetes. Studies will be designed to investigate whether epigenetic regulation of PPARgamma regulates the formation of bad versus good macrophage in genetically-engineered cell and mouse models. Accomplishment of the proposed research will reveal a novel mechanism underlying obesity-induced inflammation and help guide the development of epigenetic regulation as new therapeutic targets in the prevention and treatment of type 2 diabetes.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
My project covers basic science of type 2 diabetes research. Although the cause of diabetes remains to be a mystery, obesity appears to play a major role in the development of diabetes due to chronic inflammation from fat tissue. My project will help disclose how obesity causes type 2 diabetes. If we have a better understanding about the mechanisms underlying obesity-induced type 2 diabetes, we can help provide strategies to prevent and treat this disease in the future.
If a person with diabetes were to ask you how your project will help them in the future,
how would you respond?
Completion of my project will help diabetic patients tremendously. We are asking questions about why and how obesity tips the balance towards the increased content of some bad immune cells in fat tissue that causes the exaggerated inflammation, eventually leading to diabetes. We will investigate whether nutritional cues (eg high fat diets) and inflammatory stress cause accumulation of bad immune cells in fat tissue in the development of type 2 diabetes. If we can find answers to these questions, we may prevent accumulation of these bad immune cells, and therefore develop new therapeutic targets against this process for the prevention and treatment of type 2 diabetes. Moreover, we will also provide solid scientific evidence that changing life style (eg eating healthy food) plays a significant role in the prevention and treatment of type 2 diabetes.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
It is really important for me to be committed to diabetes research personally. My grandmother died of diabetes-related stroke when I was young. I have several close friends and relatives (including my mother-in-law) who have diabetes. Therefore, I have witnessed in the first hand their suffering from this disease. This award will play a significant role in my research efforts in fighting diabetes. This award will allow me to concentrate on the investigation of mechanisms underlying obesity-related type 2 diabetes, which inflicts my friends, relatives and many others in the world. If we have a valuable insight into the causes of the disease, we are treading toward the right direction and may soon have a cure against it.
In what direction do you see the future of diabetes research going?
Diabetes is a complex disease that results from gene and environment interaction. While numerous studies have been devoted to the evaluation of genetic factors related to diabetes, much less is known about epigenetic regulation, a term used to describe how gene expression is regulated by environmental factors such as diets without alterations in the DNA sequence. Epigenetic regulation essentially links the environmental factors such as high fat diets to diabetes. Therefore, I think that epigenetics will be a hot area in diabetes research in the future and that the findings will help guide the development of epigenetic regulation as new therapeutic targets in the prevention and treatment of type 2 diabetes.
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