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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL096834-06
Application #
8651528
Study Section
Special Emphasis Panel (ZHL1-CSR-U (F1))
Program Officer
Colombini-Hatch, Sandra
Project Start
2010-04-01
Project End
2015-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
6
Fiscal Year
2014
Total Cost
$137,445
Indirect Cost
$10,070
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Baggish, Aaron L; Park, Joseph; Min, Pil-Ki et al. (2014) Rapid upregulation and clearance of distinct circulating microRNAs after prolonged aerobic exercise. J Appl Physiol (1985) 116:522-31
Hale, Andrew; Lee, Changjin; Annis, Sofia et al. (2014) An Argonaute 2 switch regulates circulating miR-210 to coordinate hypoxic adaptation across cells. Biochim Biophys Acta 1843:2528-42
Bertero, Thomas; Lu, Yu; Annis, Sofia et al. (2014) Systems-level regulation of microRNA networks by miR-130/301 promotes pulmonary hypertension. J Clin Invest 124:3514-28
Maron, Bradley A; Oldham, William M; Chan, Stephen Y et al. (2014) Upregulation of steroidogenic acute regulatory protein by hypoxia stimulates aldosterone synthesis in pulmonary artery endothelial cells to promote pulmonary vascular fibrosis. Circulation 130:168-79
Cottrill, Katherine A; Chan, Stephen Y; Loscalzo, Joseph (2014) Hypoxamirs and mitochondrial metabolism. Antioxid Redox Signal 21:1189-201
Snow, Jonathan W; Hale, Andrew E; Isaacs, Stephanie K et al. (2013) Ineffective delivery of diet-derived microRNAs to recipient animal organisms. RNA Biol 10:1107-16
Nallamshetty, Shriram; Chan, Stephen Y; Loscalzo, Joseph (2013) Hypoxia: a master regulator of microRNA biogenesis and activity. Free Radic Biol Med 64:20-30
Parikh, Victoria N; Chan, Stephen Y (2013) Analysis of microRNA niches: techniques to measure extracellular microRNA and intracellular microRNA in situ. Methods Mol Biol 1024:157-72
Cottrill, Katherine A; Chan, Stephen Y (2013) Metabolic dysfunction in pulmonary hypertension: the expanding relevance of the Warburg effect. Eur J Clin Invest 43:855-65
Baggish, Aaron L; Hale, Andrew; Weiner, Rory B et al. (2011) Dynamic regulation of circulating microRNA during acute exhaustive exercise and sustained aerobic exercise training. J Physiol 589:3983-94

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