PDGF-Receptor regulation in Cocaine and Tat mediated Smooth Muscle Hyperplasia

描述（由申请人提供）：在抗逆转录病毒治疗时代，与获得性免疫缺陷综合征相关的并发症已从感染性并发症演变为因生存期延长而引起的并发症。这种转变的一个主要例子是人类免疫缺陷病毒（HIV）相关的肺动脉高压（PAH）。最近有报道称，多达35%的无症状艾滋病毒阳性者的肺动脉压升高，这表明HIV-PAH是一个比以前认为的更可怕的问题。此外，虽然肺血管功能障碍的出现与HIV感染的途径无关，但在静脉吸毒者（IVDU）中更常见。不幸的是，尽管在过去几年中在治疗方面取得了重大的临床进展，但HPAH的预后仍然很差，患者最终死于PAH，而不是与HIV感染相关的并发症。HPAH的发生、发展和发病率增加的确切机制仍有待阐明。我们的长期目标是从机制上了解HIV- 1和滥用药物如何相互作用并促进PAH的发病机制。认为异常平滑肌细胞增殖/迁移在导致PAH相关肺血管阻力增加的血管重塑中起关键作用。我们观察到与HIV非吸毒者相比，HIV感染的静脉吸毒者肺切片中肺动脉病变伴平滑肌增生增加。我们最近的工作进一步支持了血小板衍生生长因子BB及其受体在HIV-蛋白达特和可卡因介导的平滑肌增生中起重要作用的情况。基于这些强有力的初步发现，本建议的目的是确定参与HIV-1蛋白达特和可卡因暴露的人pSMC中PDGF受体（PDGFR）表达和活化调节的细胞和分子机制。这一目标将通过实现两个具体目标来实现。在第一个目标中，我们将确定细胞内活性氧物质参与达特和/或可卡因介导的对PDGFR信号传导的影响。在第二个目标中，我们提出描绘的作用，细胞外基质蛋白，腱生蛋白-C，在达特和可卡因介导的激活PDGFR轴。这些研究具有创新性，因为它们将首次尝试在理解可卡因和病毒蛋白相互作用中涉及的上游信号传导途径方面取得进展，导致与HIV-PAH相关的平滑肌增生，而不是专注于终末期疾病标志物。拟议的研究是重要的，因为它将提供一个更完整的了解，在存在和不存在可卡因滥用的情况下，与艾滋病毒相关的PAH的发展致病机制。因此，在靶向治疗的发展和与HPAH相关的并发症的理解的重要进展，预计在未来，这是相关的NIH的使命开发的基础知识，这将可能有助于减少人类残疾的负担。 公共卫生相关性：拟议的研究将对人类健康产生重要的积极影响，因为所确定的机制和所涉及的分子预计将为治疗干预提供新的靶点，这将有助于越来越多的艾滋病毒感染者和/或静脉吸毒者获得肺动脉高压。此外，这些结果将从根本上推动心肺血管研究领域的发展。

DESCRIPTION (provided by applicant): The complications associated with acquired immune deficiency syndrome in the anti-retroviral therapy era have evolved from those of an infectious nature to ones stemming from consequences of prolonged survival. A prime example of this shift is human-immunodeficiency virus (HIV)-related pulmonary arterial hypertension (PAH). Recent reports of elevated pulmonary artery pressures in as many as 35% of asymptomatic HIV- positive individuals suggests that HIV-PAH is a more formidable problem than previously believed. Furthermore, while pulmonary vascular dysfunction arises independently of the route of HIV-infection, it is more common in intravenous drug users (IVDU). Unfortunately, despite major clinical advances in therapy over the past few years, the prognosis of HPAH remains poor and patients end up dying from PAH rather than complications related to HIV-Infection. The precise mechanism involved in initiation, progression and increased incidence of HPAH still remains to be elucidated. Our long term goal is to understand mechanistically how HIV- 1 and drugs of abuse interact and contribute to the pathogenesis of PAH. Abnormal smooth muscle cell proliferation/migration are considered to play a key role in vascular remodeling that lead to increased pulmonary vascular resistance associated with PAH. We observed increased pulmonary arteriopathy with smooth muscle hyperplasia in human lung sections from HIV-infected IVDUs compared to HIV non-drug users. Our recent work furthermore bolsters the case that platelet-derived growth factor BB and its receptor play a prominent role in the HIV-protein Tat and cocaine mediated smooth muscle hyperplasia. Based on these strong preliminary findings, the objective of this proposal is to determine the cellular and molecular mechanism(s) involved in the regulation of expression and activation of PDGF-receptors (PDGFR) in the HIV-1 protein Tat and cocaine exposed human pSMCs. This objective will be accomplished by pursuing two specific aims. In the first aim we will determine the involvement of the intracellular reactive oxygen species in the Tat and/or cocaine mediated effect on PDGFR signaling. In the second aim we propose to delineate the role of the extracellular matrix protein, tenascin-C, in Tat and cocaine mediated activation of the PDGFR axis. These studies are innovative because they will be a first attempt to make progress in understanding the upstream signaling pathways involved in the interaction of cocaine and viral protein that results in smooth muscle hyperplasia associated with HIV-PAH, rather than focusing on the end stage disease markers. The proposed research is significant because it will provide a more complete understanding of pathogenic mechanisms involved in the development of HIV-associated PAH in the presence and absence of cocaine abuse. Thus, important advances in the development of targeted therapies and understanding of complications associated with HPAH are expected in the future which is relevant to the NIH's mission of developing fundamental knowledge that will potentially help reduce the burdens of human disability. PUBLIC HEALTH RELEVANCE: The proposed research will have an important positive impact on human health because the identified mechanism(s) and the molecules involved are expected to provide new targets for therapeutic interventions that will aid the growing number of HIV-infected and/or intravenous drug users, who acquire pulmonary arterial hypertension. In addition, the results will fundamentally advance the field of cardio-pulmonary vascular research in general.