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

可卡因和 Tat 介导的平滑肌增生中 PDGF 受体的调节

基本信息

批准号：
8231329
负责人：
Navneet Kaur Dhillon
金额：
$ 14.1万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8231329
关键词：
Acquired Immunodeficiency Syndrome Anti-Retroviral Agents Arterial Disorder Blood Vessels Cardiopulmonary Case Study Cell Proliferation Cells Clinical Cocaine Cocaine Abuse Data Development Disease Disease Marker Drug abuse Extracellular Matrix Extracellular Matrix Proteins Functional disorder Future Goals HIV HIV-1 Health Human Hyperplasia Incidence Individual Infection Intervention Knowledge Lead Ligands Literature Lung Mediating Mission Molecular Nature Oxidation-Reduction Pathogenesis Patients Platelet-Derived Growth Factor Platelet-Derived Growth Factor Receptor Play Probability Protein Tyrosine Kinase Pulmonary Hypertension Pulmonary Vascular Resistance Pulmonary artery structure Reactive Oxygen Species Receptor Activation Receptor Protein-Tyrosine Kinases Receptor Signaling Regulation Reporting Research Risk Factors Role Route Signal Pathway Signal Transduction Smooth Muscle Smooth Muscle Myocytes Tenascin Therapeutic Intervention Time United States National Institutes of Health Vascular Diseases Vascular remodeling Viral Proteins Virus Diseases Work base cocaine exposure disability drug of abuse end stage disease infancy innovation intravenous drug use intravenous drug user migration non-drug novel novel therapeutics outcome forecast platelet-derived growth factor BB pressure public health relevance pulmonary arterial hypertension receptor response stem tat Protein vascular smooth muscle cell proliferation

项目摘要

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.

描述（由申请人提供）：在抗逆转录病毒疗法中与获得的免疫缺陷综合征相关的并发症已经从感染性质的时代演变为由于长期生存的后果而导致的。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）。最近有多达35％的无症状HIV阳性个体中肺动脉压力升高的报道表明，HIV-PAH比以前认为的更为巨大的问题。此外，虽然肺血管功能障碍独立于HIV感染途径，但在静脉吸毒者（IVDU）中更常见。不幸的是，尽管过去几年在治疗方面取得了重大临床进展，但HPAH的预后仍然很差，患者最终死于PAH，而不是与HIV感染有关的并发症。 HPAH的起始，进展和增加涉及的确切机制仍然有待阐明。我们的长期目标是从机械上理解HIV-1和滥用药物如何相互作用并有助于PAH的发病机理。平滑肌细胞增殖/迁移异常被认为在血管重塑中起关键作用，从而导致与PAH相关的肺血管抗性增加。我们观察到与HIV非药物使用者相比，来自HIV感染的IVDU的人类肺部肺部肺动脉疾病增加了平滑肌增生。我们最近的工作进一步增强了血小板衍生的生长因子BB及其受体在HIV蛋白TAT和可卡因介导的平滑肌增生中起重要作用的情况。基于这些强烈的初步发现，该提案的目的是确定与HIV-1蛋白TAT和可卡因暴露于HIV-1蛋白TAT中PDGF受体（PDGFR）调节的细胞和分子机制。该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和/或可卡因介导的对PDGFR信号的影响。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，因为它们将是首次尝试了解可卡因和病毒蛋白相互作用的上游信号通路，从而导致与HIV-PAH相关的平滑肌增生，而不是专注于终端阶段疾病标志物。拟议的研究之所以重要，是因为它将在存在和不存在可卡因滥用的情况下对与HIV相关的PAH发展涉及的致病机制有更全面的了解。因此，未来期望有针对性疗法的发展和对与HPAH相关的并发症的理解的重要进展，这与NIH的使命是发展基本知识的使命，这有可能有助于减轻人类残疾的负担。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，因为所鉴定的机制和所涉及的分子有望为治疗干预提供新的目标，这将有助于越来越多的HIV感染和/或静脉注射。吸毒者，获得肺动脉高压。此外，总体上将从根本上推进心肺血管研究的领域。