Potthoff, Matthew , PhD
Targeting the transcription factor Tox as a therapeutic for nonalcoholic fatty liver disease
General Research Subject: Insulin Resistance Pre Diabetes
Focus: Integrated Physiology, Integrated Physiology\Fatty Acid Metabolism, Integrated Physiology\Liver, Obesity, Obesity\Animal Models
Type of Grant: Junior Faculty
Project Start Date: July 1, 2013
Project End Date: June 30, 2016
The scope of the metabolic disease epidemic is staggering, with the latest projections estimating that there will be 2.16 billion overweight and 1.12 billion obese individuals globally by 2030. Obesity increases the risk of developing nonalcoholic fatty liver disease (NAFLD) which is the most common chronic liver disease in the United States, affecting 20-30% of adults, and is a major risk factor for the development of type 2 diabetes. Despite the prevalence and severity of excessive deposition of fat in the liver, the molecular mechanisms of NAFLD remain poorly understood, and a pharmacologic therapy does not exist.
In an effort to understand the molecular mechanisms of NAFLD, we identified Tox (thymocyte selection-associated high mobility group box) as a hepatic transcription factor that is strongly induced during NAFLD. Our preliminary studies demonstrate that diet induced obese mice that lack Tox are resistant to the development of fatty liver and are more insulin sensitive relative to controls. The purpose of this proposal is to elucidate the role of Tox in the liver and to determine the mechanism whereby it prevents fatty liver disease. Using novel genetic mouse models and state-of-the art metabolic studies, we will provide a comprehensive analysis of the role of Tox in regulating hepatic metabolism. These studies will provide fundamental insights into the mechanism of this transcription factor and could lead to the identification of a novel target for the treatment of NAFLD.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
The research in this grant proposal addresses novel strategies for the treatment of nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes. Tox (thymocyte selection-associated high mobility group box) is a hepatic transcription factor that is strongly induced during NAFLD and our preliminary data suggests it plays an important role in the development of NAFLD. These studies will provide fundamental insights into the mechanism of this transcription factor and could lead to the identification of a novel target for the treatment of NAFLD.
If a person with diabetes were to ask you how your project will help them in the future,
how would you respond?
Our studies could identify a novel drug target to improve insulin sensitiivty and treat diabetes.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
Diabetes and its sequelae are a threat to the health and economy of our country. The prevelance of diabetes is growing and most people, including myself, have family members with diabetes or have lost a family member due to diabetes-related complications. Therefore, it's an important area of research that has the potential to have a great impact on medicine.
In what direction do you see the future of diabetes research going?
I think diabetes research will continue to expand in a couple of areas. First, I believe research examining the mechanisms regulating metabolic rate (both peripheral and central mechanisms) will lead to the identification of novel pharmacologcial approaches for treating type 2 diabetes. The second area of diabetes research I envision expanding is the development of social and behavioral strategies to both combat and prevent obesity and type 2 diabetes.
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