Viral Protein Mediators of HIV-Related Pulmonary Hypert*

HIV 相关肺动脉高压的病毒蛋白介质*

• 批准号: 7124310
• 负责人: Joseph A Lasky
• 金额: $ 39.88万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-29 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7124310
• 关键词: HIV infections; angiogenesis; antiAIDS agent; cardiovascular disorder risk; cell line; cell surface receptors; comorbidity; genetically modified animals; human herpesvirus 8; human immunodeficiency virus 1; hypoxia; laboratory mouse; pathologic process; pulmonary artery; pulmonary hypertension; respiratory function; respiratory pharmacology; vascular endothelium; vascular smooth muscle; virus protein; virus receptors

DESCRIPTION (provided by applicant): Pulmonary arterial hypertension (PAH) involves pathological remodeling of the lung vasculature and frequently results in significant disability and death. Patients infected with HIV have a higher than expected incidence of PAH. This proposal will focus specifically on mechanisms through which viral gene products expressed in patients infected with HIV-1 predispose the host to develop PAH. In addition, this proposal will explore the modulatory effects of current highly active retroviral therapy (HAART) for the treatment of HIV-1 on these mechanisms. Tat is an essential regulatory protein responsible for transcriptional activation of HIV-1. Defining how Tat modulates endothelial cell function towards the development of PAH, alone or together with other peptide factors elevated in the serum of HIV+ patients, in vitro and in vivo, is a focus of this proposal. Importantly, patients infected with HIV are commonly co-infected with human herpesvirus-8 (HHV-8). HHV-8 is known to localize to the lung endothelium, is associated with both HIV-related pulmonary hypertension (HRPH) and idiopathic pulmonary artery hypertension (iPAH), and expresses a viral G-protein coupled receptor (vGPCR) that induces angioproliferative disease. The central hypothesis to be tested in this proposal is that HHV-8 vGPCR togther with Tat predispose an individual to develop HRPH. In keeping with the directives of this RFA, the approach will study the effects of HHV-8 vGPCR, Tat, and HAART on pulmonary vascular endothelial cells and smooth muscle cells derived from humans. The biological significance of findings from the in vitro studies will be evaluated in vivo using a murine hypobaric hypoxia model of PAH because hypoxic stress occurs in patients with AIDS. This proposal brings together the collaborative expertise of 4 NIH-funded investigators, with complementary skills and experience pertaining toangiogenesis, vascular biology, and pharmacology to address this important clinical malady. The experiments to address these Specific Aims will define the role of vGPCR, Tat and HAART drugs in the development of HRPR and advance our understanding of the pathogenesis of this fatal disease, which in turn will eventuate in more effective treatments for PAH.

描述（由申请人提供）：肺动脉高压（PAH）涉及肺脉管系统的病理重塑，并且经常导致严重的残疾和死亡。感染HIV的患者的PAH高于预期的发生率。该提案将专门集中于在感染HIV-1的患者中表达的病毒基因产物易于发育PAH的机制。此外，该建议将探讨当前高度活性逆转录病毒疗法（HAART）对HIV-1治疗这些机制的调节作用。 TAT是负责HIV-1转录激活的必不可少的调节蛋白。定义TAT如何调节内皮细胞功能，以单独或与其他肽因子在体外和体内升高的其他肽因子的发展，这是该提议的重点。重要的是，感染HIV的患者通常与人疱疹病毒8（HHV-8）共同感染。已知HHV-8与肺部内皮定位，与HIV相关的肺动脉高压（HRPH）和特发性肺动脉高压（IPAH）均与病毒G蛋白偶联受体（VGPCR）相关。在该提案中要检验的中心假设是HHV-8 VGPCR具有tat易感性的人来发展HRPH。为了与该RFA的指示保持一致，该方法将研究HHV-8 VGPCR，TAT和HAART对肺血管内皮细胞和来自人类的平滑肌细胞的影响。从体外研究中发现的生物学意义将在体内使用PAH的鼠低氧缺氧模型在体内评估，因为AIDS患者发生低氧应激。该提案汇集了4位由NIH资助的研究人员的合作专业知识，并具有有关to虫发生，血管生物学和药理学的补充技能和经验，以解决这一重要的临床疾病。解决这些特定目标的实验将定义VGPCR，TAT和HAART药物在HRPR发展中的作用，并促进我们对这种致命疾病发病机理的理解，这反过来又将在PAH的更有效的治疗中发生。