DIRECT EFFECTS OF ANTIRETROVIRAL THERAPY ON CARDIAC ENERGY HOMEOSTASIS

抗逆转录病毒治疗对心脏能量稳态的直接影响

基本信息

批准号：
8502188
负责人：
PAUL W HRUZ
金额：
$ 36.18万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-20 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8502188
关键词：
Acute Adult Affect Age Animals Atazanavir Biological Models Cardiac Cardiac Myocytes Cardiomyopathies Cardiovascular Diseases Cell Fractionation Cell membrane Chronic Chronic Disease Chronic stress Clinical Trials Congenital Heart Defects Defect Deoxyglucose Development Diabetes Mellitus Dilated Cardiomyopathy Energy Metabolism Event Exhibits Exposure to Fractionation Functional disorder GLUT4 gene Glucose Glucose Transporter Goals HIV HIV Infections HIV Protease Inhibitors HIV therapy Harvest Health Care Costs Heart Heart Diseases Heart failure Homeostasis Immunofluorescence Microscopy In Situ In Vitro Individual Infarction Injury Insulin Resistance Interruption Lead Left Lopinavir/Ritonavir Measures Metabolic Mitochondria Modeling Molecular Morbidity - disease rate Mus Myocardial Myocardial Infarction Myocardium Non-Insulin-Dependent Diabetes Mellitus Nucleosides Patients Pharmaceutical Preparations Phosphorylation Prevention Protease Inhibitor Quality of life Research Reverse Transcriptase Inhibitors Risk SLC2A1 gene Stress Testing Therapeutic Ventricular Western Blotting Work acute stress aging population antiretroviral therapy base detection of nutrient exenatide fatty acid metabolism glucagon-like peptide 1 glucose transport glucose uptake heart disease risk heart function improved in vivo injured insight insulin sensitivity insulin signaling lifetime risk mimetics mortality novel therapeutic intervention prevent protein distribution release of sequestered calcium ion into cytoplasm uptake

项目摘要

Project Summary The long-term goals of this project are to characterize the influence of antiretroviral therapies on myocardial energy homeostasis and to elucidate how these changes in substrate delivery adversely affect cardiac function in the stressed heart. The studies in this proposal are intended to establish direct effects of HIV protease inhibitors (PIs) on heart function in the setting of concomitant myocardial stress or injury, to identify the molecular mechanism(s) that are responsible for these changes, and to provide effective therapeutic strategies to prevent or ameliorate cardiac dysfunction. We hypothesize that drug-induced alterations in normal substrate delivery and/or utilization in the setting of acute and chronic stress impair contractile function, resulting in increased morbidity and mortality. We further hypothesize that the ability to increase myocardial glucose uptake will improve cardiac function and survival. To test these hypotheses, the effects of PIs on cardiac function and survival will be tested in murine models of dilated cardiomyopathy and myocardial infarction. The ability of PIs to affect nutrient sensing, alter insulin signaling, impair glucose uptake, and change myocardial calcium flux will be investigated both in vitro and in an isolated working heart model system. Finally, the ability of the incretin mimetic exenatide to improve insulin sensitivity and prolong survival in PI-treated mice will be tested. Taken together, these studies will provide new insights regarding the direct contribution of antiretroviral therapy to cardiac-related morbidity and mortality and will provide a rationale basis for efforts to improve the quality of life of HIV infected individuals at increased risk for the development of cardiovascular disease.

项目摘要该项目的长期目标是表征抗逆转录病毒疗法对心肌的影响能量稳态，并阐明底物递送中这些变化如何不利影响心脏功能在紧张的心中。该提案中的研究旨在建立HIV蛋白酶的直接影响在伴随心肌应激或损伤的情况下，抑制剂（PI）对心脏功能负责这些变化并提供有效治疗策略的分子机制预防或改善心脏功能障碍。我们假设药物诱导的正常底物改变在急性和慢性压力的情况下的交付和/或利用会损害收缩功能，从而导致发病率和死亡率增加。我们进一步假设增加心肌葡萄糖的能力摄取将改善心脏功能和生存。为了检验这些假设，PI对心脏的影响功能和存活率将在扩张的心肌病和心肌梗塞的鼠模型中进行测试。这 PI影响营养感应，改变胰岛素信号，损害葡萄糖吸收并改变心肌的能力钙通量将在体外和孤立的工作心脏模型系统中研究。最后，能力肠降直直染蛋白模拟烯层以提高胰岛素敏感性和PI-处理小鼠的延长存活率测试。综上所述，这些研究将提供有关抗逆转录病毒直接贡献的新见解治疗与心脏有关的发病率和死亡率，并将为改善改善的努力提供理由的基础艾滋病毒感染的个体的生活质量增加了心血管疾病发展的风险。