Wang, Yong-Xiao , Ph.D.
Role of FKBP12.6 in the enhanced Ca2+ and contractile responses in diabetic cerebral artery myocytes
General Research Subject: Both Type 1 And Type 2 Diabetes
Type of Grant: Basic Science
Project Start Date: January 1, 2011
Project End Date: December 31, 2013
Patients with diabetes are several times more likely to have and to die from the brain vascular diseases. The accompanying brain vascular diseases may occur due to abnormally increased intracellular calcium ion level and associated contraction in smooth muscle cells of cerebral arteries (the blood vessels that supply oxygen and other nutrients to the brain). However, the cellular and molecular mechanisms for the abnormally increased intracellular calcium ion level and associated contraction are largely unknown, and the prevention and treatment of the accompanying brain vascular diseases remain major problems in diabetic patients. The purpose of this study is to test the novel and exciting hypothesis that the generation of mitochondrial reactive oxygen species (ROS, the highly reactive molecules that are involved in numerous physiological and pathological cellular responses) is significantly increased to dissociate FK506 binding protein 12.6, an important endogenous inhibitor of ryanodine-sensitive intracellular calcium release channels (normally called ryanodine receptors), from ryanodine receptors in smooth muscle cells of cerebral arteries, leading to the channel hyperfunction, mediating the abnormally increased intracellular calcium ion level and associated contraction. We will conduct the proposed experiments using the state-of-art biophysical, biochemical and genetic approaches. The findings from this study will greatly extend our understanding of the cellular and molecular processes for the onset and progress of the brain vascular diseases in diabetes, and may help to identify novel therapeutic strategies for diabetic vascular diseases.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
My research project primarily covers: (1) the cellular and molecular processes for the onset and progress of cerebral and other vascular diseases in diabetes, and (2) the identification of novel therapeutic strategies for diabetic vascular (particularly cerebrovascular) diseases. The specific objective of this project is to determine the potentially novel and important role of FK506 binding protein 12.6 and associated ryanodine-sensitive intracellular calcium release channels (ryanodine receptors) in the abnormally increased intracellular calcium ion level and contraction in diabetic cerebral vascular smooth muscle cells.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
It is well known that patients with diabetes are several times more likely to have and to die from the cerebral and other vascular diseases. However, the underlying cellular and molecular mechanisms are elusive, and the preventions and treatments of the accompanying vascular diseases remain major problems in diabetic patients. In this research project, we utilize multiple state-of-art biophysical, biochemical and genetic approaches to test the novel and exciting hypothesis that the two important calcium signaling molecules, FK506 binding protein 12.6 and ryanodine-sensitive intracellular calcium release channel, may play an essential role in abnormally increased contraction in cerebral vascular smooth muscle cells and associated vascular diseases in diabetes. The findings from the proposed experiments will greatly extend our understanding of the cellular and molecular processes for the onset and progress of the brain vascular diseases in diabetes, and may create new and effective drugs for the prevention and treatment of cerebral and other vascular diseases in 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, a devastating disease that affects >130 millions of people worldwide and incurs enormous healthcare costs, significantly increases the mortality and morbidity from cerebral and other vascular diseases. However, the cellular and molecular mechanisms for diabetic vascular diseases are largely unknown, and there are no effective prevention and treatment for the inflicted vascular diseases.
I have aligned myself with an expert in the field of Ca2+ signaling and ion channels in vascular and other smooth muscle cells, as evident by a continuous track record of research funding and publications in peer-reviewed journals. Based on our previous work and preliminary data, we hypothesize that FK506 binding protein 12.6 and ryanodine receptor are both crucial for the onset and progress of diabetic vascular diseases.
Accordingly, it is timely and necessary to conduct rigorous studies to test the aforementioned, innovative and exciting hypothesis. This prestigious award enables me to take this task. It can successfully expand my research into the field of diabetes, in which I have been showing a long-standing interest and seeking to make significant contributions.
In what direction do you see the future of diabetes research going?
Cerebral and other vascular diseases are the main causes of sickness, disability, hospitalization and death worldwide, and diabetes significantly increases the mortality and morbidity from vascular diseases. Thus, one of the major directions for the future diabetes research is to fully elucidate the molecular mechanisms underlying cerebral and other vascular diseases. Studies aimed at creating effective preventions and treatments continue to be a major direction. Other major directions are to completely understand the pathological genesis of dysfunctions of pancreas beta-cells and to identify new strategies to prevent and cure the dysfunctions of pancreas beta-cells.
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