The applicant has designed this proposal to be an intensive educational and research experience that will allow him to earn key skills to become an independent translational investigator applying the tools of computational genomics and bioinformatics to the study vascular biology and the development of atherosclerosis. To this end, the Medical College of Wisconsin provides an ideal setting for this training. The applicant's mentor, Dr. David Gutterman, is an internationally recognized expert in the study of endothelial function. Through collaborations with Drs. UN Broeckel, Daniel Beard, and Craig Struble, he will receive exceptional training in genomic research and have wide exposure to experts in genetic research and the field of bioinformatics. The vascular endothelium plays a key role in maintaining vascular homeostasis. Endothelium-derived nitre oxide (NO) is a key paracrine actor responsible for maintaining endothelial homeostasis. Excessive reactive oxygen species (ROS) production in Type II diabetics leads to a decrease in bioavailable NO, making the endothelium """"""""dysfunctional"""""""". This leads to phenotypic changes that promote the development of atherosclerosis. Recent data suggest hyperpolarization of the inner mitochondrial membrane is an important source of excessive ROS in type 2 diabetics. Excessive ROS leads to a loss of mitochondria mass, altered transcription of mitochondrial-associated genes, and finally a loss of bioavailable NO . The applicant has designed a set of investigations to assess novel markers of mitochondrial homeostasis (mitochondrial membrane potential, mitochondrial mass, mitochondrial ROS production, and oxidative phophorylation- related gene transcription) in type 2 diabetics and healthy humans. First, we will compare these measures of mitochondrial homeostasis to measures of endothelial function in diabetics and non-diabetics. Second, we will determine whether interfering with mitochondrial hyperpolarization that occurs in diabetes with by partial uncoupling of oxidative phosporylation improves endothelial function and reduces ROS production in these patients.
The incidence of Type 2 diabetes continues to rise, and with this rise comes an associated increase in risk for cardiovascular complications. These studies offer valuable insight into the role of mitochondria in endothelial regulation and may reveal novel markers of risk and targets for therapy.
|Fetterman, Jessica L; Holbrook, Monica; Westbrook, David G et al. (2016) Mitochondrial DNA damage and vascular function in patients with diabetes mellitus and atherosclerotic cardiovascular disease. Cardiovasc Diabetol 15:53|
|Mohandas, Appesh; Suboc, Tisha B; Wang, Jingli et al. (2015) Mineralocorticoid exposure and receptor activity modulate microvascular endothelial function in African Americans with and without hypertension. Vasc Med 20:401-8|
|Suboc, Tisha B; Strath, Scott J; Dharmashankar, Kodlipet et al. (2014) Relative importance of step count, intensity, and duration on physical activity's impact on vascular structure and function in previously sedentary older adults. J Am Heart Assoc 3:e000702|
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|Dharmashankar, Kodlipet; Welsh, Aimee; Wang, Jingli et al. (2012) Nitric oxide synthase-dependent vasodilation of human subcutaneous arterioles correlates with noninvasive measurements of endothelial function. Am J Hypertens 25:528-34|
|Farb, Melissa G; Ganley-Leal, Lisa; Mott, Melanie et al. (2012) Arteriolar function in visceral adipose tissue is impaired in human obesity. Arterioscler Thromb Vasc Biol 32:467-73|
|Wang, Jingli; Alexanian, Anna; Ying, Rong et al. (2012) Acute exposure to low glucose rapidly induces endothelial dysfunction and mitochondrial oxidative stress: role for AMP kinase. Arterioscler Thromb Vasc Biol 32:712-20|
|Kizhakekuttu, Tinoy J; Wang, Jingli; Dharmashankar, Kodlipet et al. (2012) Adverse alterations in mitochondrial function contribute to type 2 diabetes mellitus-related endothelial dysfunction in humans. Arterioscler Thromb Vasc Biol 32:2531-9|
|Thijssen, Dick H J; Black, Mark A; Pyke, Kyra E et al. (2011) Assessment of flow-mediated dilation in humans: a methodological and physiological guideline. Am J Physiol Heart Circ Physiol 300:H2-12|
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