Functions of the Hypoxia-Induced MicroRNA-210 in Pulmonary Vascular Endothelium

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DESCRIPTION (provided by applicant): A five year training program is proposed to develop a career in academic cardiology with a focus on pulmonary vascular function and disease. The principal investigator is a graduate of the Medical Scientist Training Program and has completed residency training in Internal Medicine and fellowship training in Cardiology (Massachusetts General Hospital, MGH). Dr. Joseph Loscalzo will serve as the primary laboratory mentor and is a recognized expert and scientific leader in vascular biology. He has successfully trained numerous postdoctoral fellows, many of whom have gone on to major scientific and leadership roles in biomedical sciences. An advisory panel of expert medical scientists will also provide further scientific and career guidance. By combining the resources of multiple Harvard-affiliated programs, this training environment is ideal to cultivate a successful research program on which to base a productive future career. The principal investigator has identified the hypoxia-induced microRNA-210 (miR-210) as a novel and essential regulator of mitochondrial metabolism and cellular respiration in hypoxic pulmonary arterial endothelial cells, via repression of the iron-sulfur cluster assembly proteins ISCU1/2. This proposal will interrogate a model whereby control of endothelial-specific phenotypes in the pulmonary vasculature depends critically upon the down-regulation of ISCU1/2 and iron-sulfur clusters by miR-210. Under conditions of normoxia and hypoxia, experiments will entail expression of miR-210 and inhibition of miR-210 in cultured pulmonary arterial endothelial cells as well as in the pulmonary vasculature of murine subjects. Phenotypes will be assessed by a combination of molecular, genetic, biochemical, and biophysical techniques. Proposed experiments listed under "Specific Aims" will elucidate the role of miR-210, ISCU1/2, and iron-sulfur clusters in the regulation of: 1) mitochondrial electron transport; 2) reactive oxygen species flux; and 3) nitric oxide bioavailability. Results will improve our molecular understanding of physiologic and pathophysiologic adaptations in the hypoxic pulmonary vasculature and may point to novel therapeutic targets. PUBLIC HEALTH RELEVANCE: This proposal will define the critical actions of a novel molecule (microRNA-210) in regulating the response to low oxygen exposure in cells that line the blood vessels of the lungs. In doing so, it is expected to improve the current understanding of the mechanisms by which low oxygen conditions affect the pulmonary vessels during normal and disease states and may point to future therapeutic targets.