LIPOPROTEIN AND ADIPOSE TISSUE METABOLISM IN HIV

HIV 中的脂蛋白和脂肪组织代谢

• 批准号: 6215526
• 负责人: LARS F BERGLUND
• 金额: $ 34.12万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-12 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6215526
• 关键词: AIDS therapy; African American; HIV infections; Hispanic Americans; adipose tissue; atherosclerosis; blood lipoprotein metabolism; body composition; clinical research; cooperative study; disease /disorder proneness /risk; drug adverse effect; drug screening /evaluation; human subject; hyperlipidemia; lipid metabolism; lipolysis; protease inhibitor

In this collaborative series of projects, we will characterize the underlying mechanisms for the metabolic complications (hyperlipidemia/body fat redistribution/insulin resistance) associated with protease inhibitors in HIV-infected subjects. Exposure of HIV-infected patients to this atherogenic metabolic state could lead to atherosclerosis and vascular disease. In one of the applications (Berglund L, PI), we propose prospective, mechanistic studies to elucidate lipoprotein and adipose tissue metabolism during protease inhibitor treatment in African American and Hispanic HIV-infected men and women. We 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 (Shachter N, PI), where existing, well-characterized cell culture and mouse models of hyperlipidemia 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), we will prospectively evaluate hyperlipidemia and insulin resistance in Caucasian HIV+ and HIV- subjects in response to protease inhibitor treatment. We 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, we will perform interventions for lipids and insulin resistance in protease inhibitor-treated HIV-infected patients. In our multitiered collaborations we 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 covers 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. We 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.

在这个合作系列项目中，我们将描述艾滋病毒感染者与蛋白酶抑制剂相关的代谢并发症（高脂血症/体脂肪重新分布/胰岛素抵抗）的潜在机制。 HIV感染者暴露于这种致动脉粥样硬化的代谢状态可能会导致动脉粥样硬化和血管疾病。 在其中一项申请（Berglund L，PI）中，我们提出了前瞻性机制研究，以阐明非裔美国人和西班牙裔 HIV 感染男性和女性在蛋白酶抑制剂治疗期间的脂蛋白和脂肪组织代谢。 我们还将确定身体脂肪重新分布和高脂血症的基线预测因子，并前瞻性地解决蛋白酶抑制剂引起的脂肪组织脂肪分解问题。 这些研究将得到基础科学项目（Shachter N，PI）的补充，其中现有的、特征良好的细胞培养物和高脂血症小鼠模型将用于探索蛋白酶抑制剂相关高脂血症背后的机制。 在这两项提案中，将探讨相同的基本假设（脂蛋白分泌增加和/或清除减少）。 此外，将启动干预实验，以利用遗传方法消除蛋白酶抑制剂诱导的高脂血症。 在第三项提案（Carr A，PI）中，我们将前瞻性评估白种人 HIV+ 和 HIV- 受试者对蛋白酶抑制剂治疗的高脂血症和胰岛素抵抗。 我们将研究蛋白酶抑制剂对脂肪组织信号通路和补体系统的影响，并确定这些因素与脂肪重新分布之间的关联。最后，我们将对接受蛋白酶抑制剂治疗的艾滋病毒感染者进行血脂和胰岛素抵抗干预。在我们的多层次合作中，我们将比较不同种族的结果，解决艾滋病毒感染者和未感染艾滋病毒受试者的蛋白酶抑制剂治疗问题，进行详细的脂肪组织和血浆脂蛋白表征，并在人类和动物模型中同时测试特定假设。 合作研究团队的专业知识涵盖与 RFA 相关的广泛领域，例如艾滋病毒治疗专业知识、身体成分、脂肪组织代谢以及脂蛋白和动脉粥样硬化方面的专业知识。 重要的是，已经建立了合作，并正在努力解决这三个应用程序中的具体假设。 我们预计，三个合作的 R01 应用之间的协同作用和相互作用将为开发新方法提供框架，以纠正接受蛋白酶抑制剂治疗的 HIV 感染者的代谢紊乱，这将影响未来的药物开发并降低心血管疾病的风险。