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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:

Tommaso Poggioli, 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?
More and more people are suffering from obesity and diabetes since we tend to eat more of the wrong kind of food while being less physically active than previous generations. The endoplasmic reticulum has been identified as one of the cellular systems that are important for translating our unhealthy habits into actual diseases such as diabetes. One of the reasons is that excessive stress on the endoplasmic reticulum leads to an increased production of fat. Thioredoxin-interacting protein (Txnip) has a relevant role in this process and is one of the proteins that are most abundantly produced in diabetic conditions. It is important for the production of fat, but it is not known how. Data from our laboratory show that changes in the activity of Txnip are associated with increased levels of endoplasmic reticulum stress and therefore in the production of fat. Our project includes experiments that would clarify if the activity of Txnip could explain the changes in fat production. Moreover, our laboratory has recently published important data on the role of Growth Differentiation Factor-11 (GDF11) in cardiovascular disease in aging mice, encouraging its investigation in the context of metabolic disorders and diabetes. We have shown that GDF11 protein levels are reduced with age in mice and that administration of this protein to aging mice rejuvenates heart, brain and skeletal muscle functions. Importantly, patients with higher incidence of cardiovascular disease show reduced levels of GDF11 in the circulation. In the context of diabetes research, our preliminary data on GDF11 suggest that administration of GDF11 in older and younger mice increases the glucose tolerance and reduces the accumulation of fat in the liver. Taken together, these data suggest a potential role of GDF11 in regulating metabolic disorders and the understanding of these mechanisms has become very relevant for the development of therapies to cure diabetes.

If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
The Txnip and GDF11 projects and the experiments included have the potential to increase our understanding of important issues in the field of obesity and diabetes, and might help to find new starting points for potential therapies. Investigating the mechanisms underlying Txnip increase in diabetic conditions will help us to produce targeted therapies aimed at restoring the healthy conditions in patients with diabetes. Moreover, the proven role of GDF11 in maintaining a ‘younger’ phenotype in brain, skeletal muscle and heart shown by our experiments has a clear potential in helping diabetic patients. Confirming our hypothesis of a direct correlation between the decrease of GDF11 protein level and the higher incidence in diabetes and cardiovascular disease in elderly patients would bring new and fundamental insights into our research and would bring us closer to developing strategies to improve the health of these patients.

Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
Diabetes is the 7th leading cause of death and recent published studies have shown that the number of patients diagnosed with diabetes has increased from 25.8 millions in 2010 to 29.1 millions in 2012 in the United States. These numbers confirm the severity of diabetes epidemiology and once again emphasize the need for investments in finding targeted and effective therapies for the treatment of metabolic disease and diabetes. My personal interest in researching the fundamental mechanisms of diabetes is driven by these critical aspects of research on and by my willingness to provide a healthier life to patients. The support of the American Diabetes Association award will allow me to continue the work on Txnip and GDF11 and understand how these molecules could benefit the treatment of diabetes and metabolic disorders. Furthermore, I believe that the support of this proposal will enable me to become an independent investigator and continue my career in cardiovascular disease and diabetes research.

In what direction do you see the future of diabetes research going?
It is well recognized that the prevalence of diabetes increases with age, with an absolute increase in incidence in the population aged 65 years and older. However, the mechanisms underlying this increase in risk remain poorly understood and no optimal interventions have been developed so far. Understanding how various mechanisms contributing to diabetes and in general to cardiovascular disease affect and are affected by advancing age is fundamental, but it is also extremely important to investigate whether these age-related diseases might arise from a common foundation. I believe that increased understanding of the pathways common to diabetes, cardiovascular disease and other morbidities might yield optimal treatments for diabetes and its complications.