Altered Nitrite Reductase Activity in Diabetics

合作研究项目#1 糖尿病患者亚硝酸还原酶活性的改变 Raymond Esquerra，主要研究者 旧金山弗朗西斯科州立大学 博士丹尼尔Kim-Shapiro，导师/合作者 维克森林大学 摘要 糖尿病是一种以持续高血糖为特征的慢性疾病， 糖尿病在美国的患病率是100%， 沿着种族线隔离，美国印第安人，非洲裔美国人和西班牙裔美国人被 1.8患糖尿病的可能性是非西班牙裔白人的2.2倍。许多有害 与血糖水平升高相关的并发症导致健康后果。在 特别是，心血管功能障碍是常见的和致命的并发症之一， 糖尿病，成年糖尿病患者的心脏病死亡率高出约2至4倍 比没有糖尿病的成年人要多。建议工作的长期目标是了解联系 心血管功能障碍和糖尿病之间的联系我们的目标是确定 增加的非酶糖化血红蛋白（HbA 1c）破坏正常的一氧化氮生理学。 确定Hb的糖化是否改变NO/Hb化学是确定Hb的糖基化是否改变NO/Hb化学的重要步骤。 发现糖尿病和心血管功能障碍之间的潜在联系。我们 中心假设是糖化血红蛋白的一氧化氮化学被改变， 因此，糖化血红蛋白水平的升高导致NO生理学的破坏， 增加糖尿病患者的心血管相关疾病。我们的理论是，通过理解 糖基化如何破坏正常的NO/Hb一氧化氮化学，我们将阐明其中一个 糖尿病患者心血管功能障碍的分子机制。的 将追求以下具体目标：1）确定糖化血红蛋白是否具有不同的亚硝酸盐 还原酶活性高于正常成人血红蛋白; 2）确定糖化血红蛋白是否具有 与正常成人血红蛋白相比，不同的NO结合和双氧合化学;以及3） 确定糖化血红蛋白与正常血红蛋白相比是否改变了变构动力学。 一个结构化的职业发展计划将使埃斯奎拉博士发展一个强大的独立 在一氧化氮生理学的指导和可持续的研究计划下，博士。 金-夏皮罗。这项研究将提供独特的生物医学研究机会， 在一个充满活力和快速发展的领域，本科生和硕士生的代表性不足 对这个国家的健康差距有重大影响的生物医学研究。

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.