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

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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.