HIV, Endothelial Dysfunction, and Insulin Resistance

HIV、内皮功能障碍和胰岛素抵抗

基本信息

批准号：
7394348
负责人：
KRISTIN E. MONDY
金额：
$ 10.98万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-04-01 至 2008-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7394348
关键词：
Advisory Committees Agonist Anti-Retroviral Agents Area Under Curve Atherosclerosis Award Biological Markers Body fat C-reactive protein Cardiac Cardiovascular Diseases Cardiovascular system Characteristics Clinical Research Clinical Trials Design Cross-Over Studies DEXA Development Diabetes Mellitus Educational Curriculum Environment Faculty Fasting Functional disorder Glucose tolerance test Goals HIV HIV diagnosis Highly Active Antiretroviral Therapy Hydroxymethylglutaryl-CoA Reductase Inhibitors Hyperlipidemia Incidence Individual Inflammation Inflammatory Insulin Insulin Resistance Lead Lipids Lipodystrophy Lipoproteins Longitudinal Studies Measures Mediating Mentors Metabolic Morbidity - disease rate Mortality Decline Natural History Numbers OGTT Observational Study PPAR gamma Pathogenesis Patients Peroxisome Proliferator-Activated Receptors Persons Pioglitazone Population Prevalence Program Development Protease Inhibitor Public Health Public Health Schools Rate Regulation Research Research Personnel Research Training Role Serum Testing Time Training Treatment Protocols Universities Washington abdominal fat antiretroviral therapy atorvastatin brachial artery cardiovascular risk factor career glucose disposal improved indexing insulin sensitivity mortality programs prospective

项目摘要

DESCRIPTION (provided by applicant): This K23 application proposes a 5-year mentored training and research plan to develop expertise in the clinical trial design, assessment, and analysis of HIV-related metabolic complications as they relate to the development and progression of endothelial dysfunction and insulin resistance. Didactic training will include coursework that is part of the Clinical Research Career Development Program at Washington University and the curriculum at St. Louis University's School of Public Health. A primary goal of this proposal is to develop a better understanding of the characteristics, natural history, cardiovascular risk, and pathogenesis of insulin resistance and endothelial dysfunction in persons on highly active antiretroviral therapy (HAART). Another goal of this proposal is to test the use of a peroxisome proliferator activated receptor gamma (PPARgamma) agonist in the therapy of these complications, thus supporting the hypothesis that PPARgamma dysregulation has an important role in the pathogenesis of insulin resistance and endothelial dysfunction in HIV-infected persons. To meet these goals, this proposal has the following specific aims: 1) Determine the temporal relationship between endothelial dysfunction and insulin resistance in HIV infected patients on HAART and its significance in terms of cardiovascular risk, 2) Evaluate the effects of a PPAR? agonist and HMG-CoA reductase inhibitor on regulation of insulin resistance, endothelial dysfunction, and biomarkers of inflammation in HIV-infected patients on HAART. Hypotheses for specific aim 1 will be tested using a 3-year prospective observational study of patients on HAART. Cardiovascular disease, worsening insulin resistance, and body fat changes will be measured by cardiac CT/carotid doppler, fasting insulin/oral glucose tolerance testing, and DEXA/CT, respectively. Hypotheses for specific aim 2 will be tested using a 48-wk. crossover trial of atorvastatin+pioglitazone vs. atorvastatin alone. Changes in insulin sensitivity/glucose disposal and body fat changes will be measured with IV glucose tolerance testing and DEXA, respectively. For both studies, brachial artery reactivity testing will be used to measure endothelial function as a surrogate for cardiovascular risk. Inflammatory biomarkers will be evaluated as surrogates for cardiovascular risk insulin resistance. The candidate will receive specific training and guidance by an exemplary mentor and faculty advisory committee and will have the full support of Washington University's outstanding research environment. This award will help fulfill the candidate's long-term career objective of becoming an independent researcher in the field of HIV-related metabolic complications.

描述（由申请人提供）：本 K23 申请提出了一项为期 5 年的指导培训和研究计划，以培养 HIV 相关代谢并发症的临床试验设计、评估和分析方面的专业知识，因为这些并发症与内皮功能障碍的发生和进展有关和胰岛素抵抗。教学培训将包括华盛顿大学临床研究职业发展计划和圣路易斯大学公共卫生学院课程的一部分。该提案的主要目标是更好地了解接受高效抗逆转录病毒治疗 (HAART) 的患者胰岛素抵抗和内皮功能障碍的特征、自然史、心血管风险以及发病机制。该提案的另一个目标是测试过氧化物酶体增殖物激活受体γ（PPARγ）激动剂在治疗这些并发症中的用途，从而支持PPARγ失调在HIV胰岛素抵抗和内皮功能障碍的发病机制中发挥重要作用的假设- 感染者。为了实现这些目标，本提案有以下具体目标：1）确定接受HAART治疗的HIV感染患者内皮功能障碍和胰岛素抵抗之间的时间关系及其在心血管风险方面的意义，2）评估PPAR的影响？激动剂和 HMG-CoA 还原酶抑制剂对接受 HAART 的 HIV 感染患者的胰岛素抵抗、内皮功能障碍和炎症生物标志物的调节作用。具体目标 1 的假设将通过一项针对 HAART 患者的为期 3 年的前瞻性观察研究进行检验。心血管疾病、胰岛素抵抗恶化和体脂变化将分别通过心脏 CT/颈动脉多普勒、空腹胰岛素/口服葡萄糖耐量测试和 DEXA/CT 来测量。具体目标 2 的假设将使用 48 周进行测试。阿托伐他汀+吡格列酮与单独阿托伐他汀的交叉试验。胰岛素敏感性/葡萄糖处理的变化和身体脂肪的变化将分别通过 IV 葡萄糖耐量测试和 DEXA 来测量。对于这两项研究，肱动脉反应性测试将用于测量内皮功能，作为心血管风险的替代指标。炎症生物标志物将作为心血管风险胰岛素抵抗的替代指标进行评估。候选人将接受模范导师和教职顾问委员会的具体培训和指导，并将得到华盛顿大学卓越研究环境的全力支持。该奖项将有助于实现候选人的长期职业目标，即成为艾滋病毒相关代谢并发症领域的独立研究员。