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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Clinical Investigator Award (CIA) (K08)
Project #
Application #
Study Section
Special Emphasis Panel (ZHL1-CSR-U (F1))
Program Officer
Colombini-Hatch, Sandra
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Brigham and Women's Hospital
United States
Zip Code
Bertero, Thomas; Oldham, William M; Cottrill, Katherine A et al. (2016) Vascular stiffness mechanoactivates YAP/TAZ-dependent glutaminolysis to drive pulmonary hypertension. J Clin Invest 126:3313-35
Parikh, Victoria N; Park, Joseph; Nikolic, Ivana et al. (2015) Brief Report: Coordinated Modulation of Circulating miR-21 in HIV, HIV-Associated Pulmonary Arterial Hypertension, and HIV/Hepatitis C Virus Coinfection. J Acquir Immune Defic Syndr 70:236-41
Bertero, Thomas; Cottrill, Katherine A; Lu, Yu et al. (2015) Matrix Remodeling Promotes Pulmonary Hypertension through Feedback Mechanoactivation of the YAP/TAZ-miR-130/301 Circuit. Cell Rep 13:1016-32
Bertero, Thomas; Cottrill, Katherine; Krauszman, Adrienn et al. (2015) The microRNA-130/301 family controls vasoconstriction in pulmonary hypertension. J Biol Chem 290:2069-85
Bertero, Thomas; Cottrill, Katherine A; Annis, Sofia et al. (2015) A YAP/TAZ-miR-130/301 molecular circuit exerts systems-level control of fibrosis in a network of human diseases and physiologic conditions. Sci Rep 5:18277
Min, Pil-Ki; Chan, Stephen Y (2015) The biology of circulating microRNAs in cardiovascular disease. Eur J Clin Invest 45:860-74
White, Kevin; Lu, Yu; Annis, Sofia et al. (2015) Genetic and hypoxic alterations of the microRNA-210-ISCU1/2 axis promote iron-sulfur deficiency and pulmonary hypertension. EMBO Mol Med 7:695-713
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
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
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

Showing the most recent 10 out of 28 publications