Probing the pore of CFTR using chemical modification

使用化学修饰探测 CFTR 的孔隙

• 批准号: 6524621
• 负责人: XUEHONG LIU
• 金额: $ 4.81万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6524621
• 关键词: Xenopus oocyte; anions; chloride channels; cysteine; membrane potentials; membrane proteins; pore forming protein; postdoctoral investigator; protein structure function; thiols

The specific aim of this proposal is to investigate potential mechanisms by which a diet in saturated fat and refined carbohydrates (sucrose) induces insulin resistance and hypertension compared to a diet high in unrefined carbohydrate and low in fat. Hypertension afflicts one quarter of the adult population in the United States and is a hallmark risk factor for myocardial infarction, stroke and congestive heart failure. Although its cause is largely unknown, it is associated with insulin resistance/ hyperinsulinemia, oxidative stress and endothelial dysfunction. The primary hypothesis' to be tested in this grant is that a high-fat, refined carbohydrate diet (HFS) increases the production of reactive oxygen/nitrogen species (e.g. ONOO-), contributing to insulin resistance, as well as sequestrating and inactivating NO leading to hypertension. To test this hypothesis, male and female rats will be raised on either the HFS or a low fat, complex carbohydrate diet (LFCC) and blood pressure will be measured via the tail-cuff and telemetry methods. Isolated arterial segments will be used to test endothelial function. Plasma/urinary measurements will assess NO metabolites, MDA and cGMP levels. Biochemical studies will be . conducted on several tissues, including aorta, heart and kidney to measure eNOS, iNOS; nNOS and SOD proteins, NOS and SOD activities, nitrotyrosine formation and tissue cGMP levels. Studies will also be conducted to Investigate the value- of dietary modification (switching to an LF(6 diet or-antioxidant supplementation) and exercise training for controlling hypertension, as well as the role of caloric restriction on the development of hypertension. The results of these studies may provide a. mechanism to explain how HFS type diets cause insulin resistance. and hypertension, and how a LFCC diet, antioxidant therapy or exercise training aid in the control of insulin resistance and hypertension.

该提案的具体目的是研究与高未精制碳水化合物和低脂肪饮食相比，饱和脂肪和精制碳水化合物（蔗糖）饮食诱发胰岛素抵抗和高血压的潜在机制。高血压困扰着美国四分之一的成年人，是心肌梗塞、中风和充血性心力衰竭的标志性危险因素。尽管其病因尚不清楚，但它与胰岛素抵抗/高胰岛素血症、氧化应激和内皮功能障碍有关。本次资助要测试的主要假设是，高脂肪、精制碳水化合物饮食 (HFS) 会增加活性氧/氮（例如 ONOO-）的产生，从而导致胰岛素抵抗，并隔离和灭活 NO导致高血压。为了检验这一假设，雄性和雌性大鼠将采用 HFS 或低脂、复杂碳水化合物饮食 (LFCC) 饲养，并通过尾套和遥测方法测量血压。分离的动脉段将用于测试内皮功能。血浆/尿液测量将评估 NO 代谢物、MDA 和 cGMP 水平。生化研究将。对包括主动脉、心脏和肾脏在内的多个组织进行测量 eNOS、iNOS； nNOS 和 SOD 蛋白、NOS 和 SOD 活性、硝基酪氨酸形成和组织 cGMP 水平。还将进行研究以调查饮食调整（改用 LF（6 饮食或抗氧化剂补充剂）和运动训练对控制高血压的价值，以及热量限制对高血压发展的作用。这些研究可能提供一种机制来解释 HFS 型饮食如何导致胰岛素抵抗和高血压，以及 LFCC 饮食、抗氧化疗法或运动训练如何帮助控制胰岛素抵抗和高血压。