The NIH Mentored Clinical Scientist Research Career Development Award proposal describes a 5-year training program for career development in academic cardiovascular medicine. The principal investigator (PI) completed a postdoctoral basic science research fellowship (2005-2008) and in July 2011 joined as Faculty in the Division of Cardiovascular Medicine at Brigham and Women's Hospital/Harvard Medical School (BWH/HMS). The PI continues an intensive research program (2010- ) designed to promote a career as an independent scientist in cardiovascular diseases. The proposed research plan affords the PI rigorous experience in cell biology, liquid chromatography-mass spectrometry (LC-MS), and cardiopulmonary hemodynamic assessment in vivo. Drs. Joseph Loscalzo and Jane Leopold will mentor the PI's scientific development during this period. Dr. Loscalzo is an internationally recognized leader in the fields of redox biology and pulmonary arterial hypertension (PAH), who has vast experience in mentoring successfully young physician-scientists. Dr. Leopold is an Associate Professor of Medicine (HMS) and an expert in the field of aldosterone (ALDO)-mediated vascular dysfunction, with a strong track record in mentorship. This proposal focuses on redox biochemistry to investigate the contribution of ALDO to the development of pulmonary vascular dysfunction in PAH;thus, co-mentorship for this proposal is uniquely suited for the PI. The Loscalzo/Leopold Cardiovascular Research Laboratory (BWH/HMS) is the site for this project and an excellent environment with the necessary resources to ensure the PI's success for achieving independence in academic medicine. PAH is a fatal disease characterized by increased pulmonary vascular endothelial reactive oxygen species (ROS) formation, decreased levels of bioavailable nitric oxide (NO.), and impaired pulmonary endothelium-dependent vasodilation. ROS-mediated modifications in the redox state of functionally essential protein cysteinyl thiols involved in NO. signaling may affect adversely vascular tone. In human pulmonary artery endothelial cells (HPAECs), endothelin- B (ETB) receptor Cys405 is functionally linked to activation of endothelial nitric oxide synthase by ETB to generate NO.. Here, we provide novel evidence to demonstrate that hyperALDO is present in PAH in vivo, which increases ROS levels in HPAECs to induce ETB disulfide bond/sulfenic acid formation and decrease ETB-dependent NO. synthesis. Thus, the central hypothesis of this proposal is that: In PAH, oxidative modification of Cys405 by hyperALDO- induced ROS formation acts as a molecular "switch" to disrupt ETB-dependent NO. generation and impair pulmonary vasodilation.
The specific aims are: (1) investigate the functional effects of ALDO-induced ETB cysteinyl thiol oxidative modification(s) in vitro;(2a) determine the contribution of hyperALDO to impaired pulmonary vascular reactivity in PAH in vivo;and (2b) investigate the therapeutic effects of ALDO antagonism for PAH in vivo. We will use two different models of PAH in rats in vivo and LC-MS to identify ETB cysteinyl thiol oxidation product(s). These studies aim to identify novel treatment targets for PAH and other vascular diseases with similar pathobiology.
Elevated blood pressure in the pulmonary circulation (pulmonary hypertension) is a major contributor to decreased quality of life and premature death in patients with common forms of heart, lung, and blood diseases. We propose that increased levels of the hormone aldosterone, known to be present in many conditions associated with pulmonary hypertension and recognized as toxic to blood vessels under these circumstances, represents a potential new treatment target for large patient populations afflicted with this disease.
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