Hypoxic inflammation, pulmonary hypertension, and HO-1

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DESCRIPTION (provided by applicant): My long-term career goal is to combine clinical practice as a pediatric intensivist, laboratory investigation directed toward answering questions raised at the bedside about the cellular and molecular mechanisms of disease, and education and mentoring of trainees in both the clinical and research arenas into long-term, fulfilling career in academic medicine. In the next five years, I hope to strengthen my skills as a pediatric intensivist but I am also committed to devoting the majority of my time to acquire the necessary skills and knowledge in order to succeed as an independent physician-scientist. Specifically, I intend to develop my technical and experimental design skills in the laboratory, increase my knowledge of basic molecular and cellular biology and animal physiology through course work, and enhance my analytical and communication skills through literature review and presentations of my data in the forums of laboratory, division, hospital, and international meetings. The environment for working toward these goals will be in the laboratory of Dr. Stella Kourembanas, a lung and vascular biologist at Children's Hospital Boston who studies the effects of hypoxia on the vasculature in order to understand the pathogenesis of hypoxia-induced pulmonary hypertension (PHTN). Exposure to chronic hypoxia causes inflammatory cell infiltrate and cytokine/chemokine expression in the lung which may play a role in a number of disease processes. Heme oxygenase-1 (HO-1) is a hypoxia-inducible enzyme with actions that protect against hypoxic inflammation and PHTN. My long-term research goal is to understand the mechanisms by which hypoxia causes PHTN and HO-1 protects against PHTN. i hypothesize that cytokines and chemokines released during hypoxic inflammation trigger changes of the pulmonary vasculature that lead to PHTN and that HO-1 interferes with the signaling mechanisms by which hypoxia induces this inflammatory cytokine and chemokine release. The specific aims of the proposed project are (i) to determine whether inflammation plays a causative role in the development of hypoxic PHTN, (ii) to investigate the mechanisms by which HO-1 inhibits inflammatory gene expression induced by hypoxia, and (iii) to evaluate the protective effects of HO-1's enzymatic products, carbon monoxide and bilirubin, on hypoxic PHTN. The experimental design employs both in vivo studies in transgenic mice and in vitro studies using adenoviral-mediated gene transfer of HO-1 in hypoxic cells. These studies will increase our understanding of hypoxia-induced inflammation, the pathogenesis of hypoxic PHTN, and the protective actions of HO-1 in both processes.