COLLABORATIVE RESEARCH PROJECT #1ALTERED NITRITE REDUCTASE ACTIVITY IN DIABETICSRaymond Esquerra, Principal InvestigatorSan Francisco State UniversityDr. Daniel Kim-Shapiro, Mentor/CollaboratorWake Forest UniversityAbstractDiabetes, a chronic disease characterized by persistent hyperglycemia, is one of the leadingcauses of morbidity and mortality in the U.S. The prevalence of diabetes in the United States issegregated along racial lines, with American Indians, African Americans, and Hispanics being1.8 to 2.2 times more likely than non-Hispanic whites to suffer from diabetes. Many detrimentalhealth consequences result from complications associated with elevated blood sugar levels. Inparticular, cardiovascular dysfunction is one of the common and deadly complications ofdiabetes, with heart disease death rates in diabetic adults being about two to four times higherthan in adults without diabetes. The long-term goal of the proposed work is to understand the linkbetween increased cardiovascular dysfunction and diabetes. Our objective is to determine howincreased nonenzymatically glycated hemoglobin (HbA1c) disrupts normal nitric oxide physiology.Determining whether the glycation of Hb alters NO/Hb chemistry is an essential step indiscovering the underlying connection between diabetes and cardiovascular dysfunction. Ourcentral hypothesis is that the nitric oxide chemistry of glycated hemoglobin is altered and,consequently, elevated levels of glycated hemoglobin result in disrupted NO physiology andincreased cardiovascular-related ailments in diabetics. Our rationale is that, by understandinghow glycation disrupts normal NO/Hb nitric oxide chemistry, we will elucidate one of themolecular mechanisms underlying the cardiovascular dysfunction prevalent in diabetics. Thefollowing specific aims will be pursued: 1) determine if glycated hemoglobin has different nitritereductase activity than normal adult hemoglobin; 2) determine if glycated hemoglobin hasdifferent 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 independentand sustainable research program in nitric oxide physiology under the mentored guidance of Dr.Kim-Shapiro. This research will provide unique biomedical research opportunities forunderrepresented undergraduate and masters students in a dynamic and quickly evolving areaof biomedical research with major implications for health disparities in this country.
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