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经从传染性的并发症演变为源于长期生存的并发症。这种转变的一个主要例子是人类免疫缺陷病毒（HIV）相关肺动脉高压（PAH）。最近有报道称，35%的无症状HIV阳性患者肺动脉压升高，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感染途径无关，但在静脉注射吸毒者（IVDU）中更为常见。不幸的是，尽管在过去几年中治疗取得了重大的临床进展，但肺动脉高压的预后仍然很差，患者最终死于肺动脉高压而不是与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。我们的长期目标是了解HIV- 1和药物滥用如何相互作用并促进PAH的发病机制。平滑肌细胞异常增殖/迁移被认为在血管重构中起关键作用，导致肺动脉高压相关肺血管阻力增加。我们观察到，与非HIV吸毒者相比，HIV感染的IVDUs的人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Tat和可卡因介导的平滑肌增生中发挥突出作用的情况。基于这些强有力的初步发现，本提案的目的是确定参与调节pdgf受体（PDGFR）在HIV-1蛋白Tat和可卡因暴露的人类pSMCs中的表达和激活的细胞和分子机制。这一目标将通过追求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在Tat和/或可卡因介导的PDGFR信号传导中的作用。在第二个目标中，我们建议描述细胞外基质蛋白tenascin-C在Tat和可卡因介导的PDGFR轴激活中的作用。这些研究具有创新性，因为它们将首次尝试了解可卡因和病毒蛋白相互作用所涉及的上游信号通路，从而导致与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致病机制，涉及艾滋病毒相关的多环芳烃在存在和不存在可卡因滥用的发展。因此，在靶向治疗的发展和对与HPAH相关的并发症的理解方面，未来有望取得重要进展，这与NIH发展基础知识的使命有关，这些知识将有可能帮助减轻人类残疾的负担。

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.