PROTEASE INHIBITOR RELATED ATHEROSCLEROSIS IN HIV

描述 （摘自申请人摘要）在这一合作系列中， 项目，调查人员将描述潜在的机制， 代谢并发症（高脂血症/体脂再分布/胰岛素 耐药性）与HIV感染受试者中的蛋白酶抑制剂相关。 在 其中一个应用程序（Berglund L，PI），研究人员提出亲， 阐明脂蛋白和脂肪组织的前瞻性机制研究 蛋白酶抑制剂治疗期间的代谢， 西班牙裔艾滋病毒感染者。 他们还将确定基线 体脂肪再分布和高脂血症的预测因子， 解决脂肪组织脂解反应蛋白酶抑制剂。 这些 研究将由基础科学项目（Schacter N，PI）补充， 在现有的，充分表征的细胞培养和小鼠模型的超， 将使用该技术探索蛋白酶抑制剂背后的机制- 相关高脂血症。 在这两个提案中，同样的基本假设 将探索（脂蛋白分泌增加和/或清除率降低）。 此外，将启动干预实验以废除蛋白酶 使用遗传学方法的代谢诱导高脂血症。 第三 建议（卡尔A，PI），他们将前瞻性评估高脂血症， 白种人HIV+和HIV-受试者对蛋白酶反应的胰岛素抵抗 抑制剂处理。 他们将讨论蛋白酶抑制剂对 脂肪组织信号通路和补体系统，并确定 这些因素与脂肪再分布之间的关系。 最后 研究人员将对血脂和胰岛素抵抗进行干预， 蛋白酶促生长剂治疗的HIV感染者。 在他们的多层 合作，他们将比较不同种族群体的结果， 蛋白酶抑制剂治疗HIV感染者和非HIV感染者， 详细的脂肪组织和血浆脂蛋白特征和测试 在人类和动物模型中同时进行特定的假设。 的 合作研究团队的专业知识涵盖广泛的相关领域， RFA，如艾滋病毒治疗专业知识，身体成分的专业知识， 脂肪组织代谢和脂蛋白以及动脉粥样硬化。 重要的是， 已经建立了合作关系，并正在努力 解决三个应用程序中的具体假设。 调查人员 希望这三个合作伙伴之间的协同作用和相互作用 R 01应用将为开发新方法提供框架， 纠正蛋白酶治疗HIV感染者的代谢紊乱 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.