Tong, Lu , MD, PhD
Role of Ubiquitin-Proteasome System in the Regulation of Vascular BK Channel Beta1 Subunit Expression in Type 2 Diabetes
General Research Subject: Type 2 Diabetes
Type of Grant: Basic Science
Project Start Date: January 1, 2012
Project End Date: December 31, 2014
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
Type 2 diabetes accounts for 90% of the total cases of diabetes mellitus and is associated with markedly increased risks of vascular complications. The large conductance Ca2+-activated K+ (BK) channels, abundantly expressed in vascular smooth muscle cells (SMCs), are a key determinant of vascular tone and tissue perfusion. Functional vascular BK channels are composed of four pore-forming alpha subunits (BK-a) and four regulatory beta1 subunits (BK-b1). BK-a activity is tightly regulated by BK-b1. However, vascular BK channel function is impaired in type 2 diabetes largely due to reduced BK-b1 expression in vascular SMCs. This project will determine the signaling pathways, particularly the reactive oxygen species (ROS) signaling-dependent pathway that regulates the BK-b1 expression in diabetic vessels. Of particular interest is to determine whether an increase of vascular BK-b1 expression using FDA-approved drugs and gene therapy will enhance BK channel activity, therefore preserve vascular function in type 2 diabetes. The proposed studies in this project have significant clinical relevant not only for better understanding of molecular mechanism of diabetic vascular BK dysfunction, but also for the discovery and development of a new strategy in the treatment of diabetic vascular complications.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Diabetic vascular dysfunction contributes to hypertension, stroke, heart attack, kidney dysfunction, mental disorder and eye complications. Although the clinical course of type 2 diabetes is usually less aggressive compared to its type 1 counterpart, the end results are equally devastating even with intensive glycemic control. The causes of diabetic vascular dysfunction involve endothelial-dependent and -independent mechanisms. The former has been well studied; however, the latter has been received less attention. Since vascular smooth muscle physiology is profoundly modulated by diabetes mellitus and the BK channel activity is a key determinant of vascular smooth muscle relaxation, we believe that vascular BK channels also play an impotent role in diabetic vascular dysfunction. The central hypothesis in this study is to test whether increase of BK-b1 expression in vascular SMCs will improve BK channel-mediated vascular relaxation in diabetes mellitus. Hence, results from this project may open doors to a new area of research and allow us to identify potential novel targets in the treatment of diabetic vascular complications.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
Diabetes mellitus has become a global epidemic. According to the National Institutes of Health estimate, about 23.6 million people suffered from diabetes mellitus in 2007, and another 59.7 million Americans were prediabetic in the United States. This figure will be more than doubled by 2030. As a fact, diabetic vascular complication has become a major cause of mortality, contributing to more than 230,000 deaths annually in the United States. As a cardiovascular electrophysiologist, I am interested in understanding how vascular smooth muscle BK channel function is regulated by diabetes mellitus and whether vascular BK channel can be considered as a therapeutic target for diabetic vascular complications. The present ADA award will help us directly address these questions and bring our research into a next level.
In what direction do you see the future of diabetes research going?
I see the further of diabetes researches must be focused on a better understanding of pathology and complications of diabetes mellitus and on the development of novel modalities of clinical therapies (gene therapy and regeneration therapy, etc.). The long-term goal is to reduce the cost of health care and to improve the quality of life in patients with diabetes mellitus.
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