PROTEASE INHIBITOR RELATED ATHEROSCLEROSIS IN HIV

描述 (改编自申请人的摘要)在这个合作系列中 项目，调查人员将确定潜在机制的特征 代谢并发症(高脂血症/体脂再分布/胰岛素 抗药性)与HIV感染者中的蛋白酶抑制剂有关。在……里面 其中一项申请(伯格伦德·L，派)，调查人员提议支持- 阐明脂蛋白和脂肪组织的自省机制研究 非裔美国人和非裔美国人在接受蛋白酶抑制剂治疗期间的代谢 感染艾滋病毒的西班牙裔男性和女性。他们还将确定基线 体脂再分布和高脂血症的预测因素，以及前瞻性的 解决脂肪组织脂肪分解对蛋白水解酶的反应。这些 研究将得到基础科学项目(Schacter N，PI)的补充， 在现有的、特征良好的细胞培养和小鼠模型中 血脂将被用来探索蛋白酶抑制剂背后的机制- 伴发高脂血症。在这两个提案中，相同的基本假设 将探索(增加脂蛋白分泌和/或降低清除量)。 此外，将启动干预实验以消除蛋白酶 用遗传学方法研究抑制剂诱导的高脂血症。在第三节 建议(CARR A，PI)，他们将前瞻性地评估高脂血症和 高加索人HIV+和HIV感染者对蛋白水解酶的胰岛素抵抗 抑制剂治疗。他们将解决蛋白水解酶抑制剂对 脂肪组织信号转导途径及其对补体系统的影响 这些因素与脂肪再分配之间的联系。最后， 研究人员将对脂类和胰岛素抵抗进行干预 蛋白水解酶抑制剂治疗艾滋病毒感染患者。在他们的多层 合作，他们将比较不同种族群体的结果，解决 人类免疫缺陷病毒感染者和非感染者的蛋白酶抑制剂治疗 详细的脂肪组织和血浆脂蛋白的特性和测试 在人类和动物模型中同时存在特定的假设。这个 合作研究团队的专业知识涵盖与以下方面相关的广泛领域 RFA，如艾滋病毒治疗专业知识，身体成分专业知识， 脂肪组织代谢和脂蛋白与动脉粥样硬化。重要的是 已经建立了合作关系，并已在努力 解决这三个应用程序中的具体假设。调查人员 期望这三个合作之间的协同和互动 R01应用程序将为开发新的方法提供一个框架 用蛋白酶治疗HIV感染者的正确代谢紊乱 抑制剂，将影响未来的药物开发，并降低风险 心血管疾病。

DESCRIPTION (Adapted from the applicant's abstract) In this collaborative series of projects, the investigators will characterize the underlying mechanisms for the metabolic complications (hyperlipidemia/body fat redistribution/insulin resistance) associated with protease inhibitors in HIV-infected subjects. In one of the applications (Berglund L, PI), the investigators propose pro- spective, mechanistic studies to elucidate lipoprotein and adipose tissue metabolism during protease inhibitor treatment in African American and Hispanic HIV-infected men and women. They will also determine baseline predictors of body fat redistribution and hyperlipidemia, and prospectively address adipose tissue lipolysis in response to protease inhibitors. These studies will be complemented by the basic science project (Schacter N, PI), where existing, well-characterized cell culture and mouse models of hyper- lipidemia will be used to explore mechanisms behind protease inhibitor- associated hyperlipidemia. In both proposals, the same fundamental hypotheses will be explored (increased lipoprotein secretion and/or decreased clearance). Further, intervention experiments will be initiated to abrogate protease inhibitor-induced hyperlipidemia using genetic approaches. In the third proposal (Carr A, PI), they will prospectively evaluate hyperlipidemia and insulin resistance in Caucasian HIV+ and HIV- subjects in response to protease inhibitor treatment. They will address effects of protease inhibitors on adipose tissue signaling pathways and on the complement system and determine the association between these factors and fat redistribution. Finally, the investigators will perform interventions for lipids and insulin resistance in protease inhibitor-treated HIV-infected patients. In their multitiered collaborations, they will compare results in different ethnic groups, address protease inhibitor treatment in HIV-infected and HIV-noninfected subjects, do detailed adipose tissue and plasma lipoprotein characterizations and test specific hypotheses simultaneously in humans and in animal models. The expertise of the collaborative research teams cover broad areas relevant to the RFA, such as HIV treatment expertise, expertise in body composition, adipose tissue metabolism and lipoproteins and atherosclerosis. Importantly, collaborations have been established and efforts are already under way to address the specific hypotheses in the three applications. The investigators expect that the synergisms and interactions between the three collaborating R01 applications will provide a framework for development of new approaches to correct metabolic derangements in HIV-infected subjects treated with protease inhibitors, will impact on future drug development and reduce the risk of cardiovascular disease.