COLLABORATIVE RESEARCH PROJECT #1 ALTERED NITRITE REDUCTASE ACTIVITY IN DIABETICS Raymond Esquerra, Principal Investigator San Francisco State University Dr. Daniel Kim-Shapiro, Mentor/Collaborator Wake Forest University Abstract Diabetes, a chronic disease characterized by persistent hyperglycemia, is one of the leading causes of morbidity and mortality in the U.S. The prevalence of diabetes in the United States is segregated along racial lines, with American Indians, African Americans, and Hispanics being 1.8 to 2.2 times more likely than non-Hispanic whites to suffer from diabetes. Many detrimental health consequences result from complications associated with elevated blood sugar levels. In particular, cardiovascular dysfunction is one of the common and deadly complications of diabetes, with heart disease death rates in diabetic adults being about two to four times higher than in adults without diabetes. The long-term goal of the proposed work is to understand the link between increased cardiovascular dysfunction and diabetes. Our objective is to determine how increased nonenzymatically glycated hemoglobin (HbA1c) disrupts normal nitric oxide physiology. Determining whether the glycation of Hb alters NO/Hb chemistry is an essential step in discovering the underlying connection between diabetes and cardiovascular dysfunction. Our central hypothesis is that the nitric oxide chemistry of glycated hemoglobin is altered and, consequently, elevated levels of glycated hemoglobin result in disrupted NO physiology and increased cardiovascular-related ailments in diabetics. Our rationale is that, by understanding how glycation disrupts normal NO/Hb nitric oxide chemistry, we will elucidate one of the molecular mechanisms underlying the cardiovascular dysfunction prevalent in diabetics. The following specific aims will be pursued: 1) determine if glycated hemoglobin has different nitrite reductase activity than normal adult hemoglobin;2) determine if glycated hemoglobin has different NO binding and dioxygenation chemistry compared to normal adult hemoglobin;and 3) determine if glycated hemoglobin has altered allosteric kinetics compared to normal hemoglobin. A structured career development plan will allow Dr. Esquerra to develop a strong independent and sustainable research program in nitric oxide physiology under the mentored guidance of Dr. Kim-Shapiro. This research will provide unique biomedical research opportunities for underrepresented undergraduate and masters students in a dynamic and quickly evolving area of biomedical research with major implications for health disparities in this country.
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