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Lee, Richard, MD

Brigham and Women's Hospital, Boston, Massachusetts

Project Title:

Regulation of Endoplasmic Reticulum Stress by Thioredoxin-Interacting Protein

Grant Number:

7-12-MN-46

Type of Grant:

Mentor-Based Postdoctoral Fellowship

General Research Subject:

Type 2 Diabetes

Project Start Date:

Jul 1, 2012

Project End Date:

Jun 30, 2016

Mentor:

Richard T. Lee, MD

Postdoctoral Fellow:

Ahmed I. Mahmoud, PhD

Focus:

Integrated Physiology, Integrated Physiology\Fatty Acid Metabolism, Obesity, Obesity\Pathogenesis, Signal Transduction (Non-Insulin Action), Signal Transduction (Non-Insulin Action)\Transgenic Models

Research Description



The epidemic of type 2 diabetes is growing world-wide, and a cellular structure called the endoplasmic reticulum has been identified as important for translating our unhealthy habits into actual diseases such as diabetes. The endoplasmic reticulum is responsible for properly folding proteins and if its folding machinery is overwhelmed, unfolded or misfolded proteins lead to a condition called endoplasmic reticulum stress. One of the consequences of this stress is an increased production of fat. Protein disulfide isomerases are proteins responsible for proper protein folding in the endoplasmic reticulum, and any protein that changes their activity could affect the endoplasmic reticulum stress level and the production of fat. Thioredoxin-interacting protein is one of the proteins most abundantly produced in diabetic tissues; it is important for the production of fat, but it is not known how. We propose that thioredoxin-interacting protein regulates fat production by regulating protein disulfide isomerase activity. We show that these proteins interact and that the resulting changes in activity are associated with increased levels of endoplasmic reticulum stress. In this proposal we will perform experiments that will clarify if the interaction between thioredoxin-interacting protein and protein disulfide isomerases could explain the changes in fat production that are associated with thioredoxin-interacting protein. These experiments have the potential to increase our understanding of important issues in diabetes, and might help to find new approaches for potential therapies.

Research Profile



What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
The endoplasmic reticulum is a structure inside the cell, and it has emerged as one of the cellular structures critically involved in diseases such as diabetes. The endoplasmic reticulum is responsible for properly folding proteins and if its folding machinery is overwhelmed, unfolded or misfolded proteins lead to a condition called endoplasmic reticulum stress. One of the surprising consequences of this stress is an increased production of fat. Protein disulfide isomerases are proteins responsible for proper protein folding in the endoplasmic reticulum, and any protein that changes their activity could affect the endoplasmic reticulum stress level and the production of fat. Thioredoxin-interacting protein is one of the proteins most abundantly produced in diabetic tissues; it is important for the production of fat, but it is not known how. We propose that thioredoxin-interacting protein regulates fat production by regulating protein disulfide isomerase activity. The proposed experiments have the potential to increase our understanding of diabetes, specifically the mechanisms that regulate increased fat production, and might help to find new approaches for potential therapies. If successful, our project will provide a new link between fat and diabetes.

If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Diabetes is associated with a variety of different metabolic problems including increased production of fat and decreased sensitivity for insulin. There are a large number of proteins and signaling pathways that are involved in the development of these complications, and they often connect in complex ways. Our project focuses on the connection between a protein called thioredoxin-interacting protein, which is markedly induced by glucose and thus highly expressed in diabetic tissues, and the development of a process called endoplasmic reticulum stress. Since we already know that endoplasmic reticulum stress plays an important role in many diabetic complications, including increased production of fat and decreased sensitivity for insulin, this project will help us to gain a deeper understanding of the mechanisms that underlie these metabolic complications. As our understanding of this pathway advances, we will hopefully be able to identify new approaches for treatment of diabetes and its metabolic complications.

Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
There is a growing epidemic of diabetes in our generation, and as doctors we see more and more patients with diabetes and its associated diseases such as heart attacks and strokes. As a physician, I see many diabetic patients, and I also have friends and relatives who are affected by this disease. Therefore, it is especially motivating to be involved in diabetes research since it addresses one of the most relevant public health issues of our time and impacts many people I know. This award will help fund a postdoctoral research fellow who will focus on advancing our understanding of the mechanisms that lead to complications of diabetes, and it is very exciting to try to make a contribution in this area.

In what direction do you see the future of diabetes research going?
In my opinion, the future of diabetes research will be two-fold. First and foremost, there should be a focus on attacking the problem on a population-wide, public health policy-related approach that should develop new strategies for prevention and adjustment of unhealthy behaviors that led us to the epidemic of diabetes. The second approach will focus on the molecular mechanisms that underlie the development of diabetes and the diabetic complications in various tissues and organs. These efforts will hopefully help us to find new ways to prevent diabetes as well as to develop treatments for patients that are suffering from diabetes. We need education, public policy, research and translation of research findings to stop this epidemic.