Dr. Robyn J. Barst Pediatric PH Research and Mentoring Fund Grant Winner 2016

Sheila Krishnan, DOSheila Krishnan, DO

Pulmonary and Critical Care Fellow
Indiana University
Title: “Hypoxia-dependent Epigenetic Modifications in the Pulmonary Vasculature”
Term: December 1, 2016 – November 30, 2016

Cordelia’s Pediatric PH Research and Mentoring Grant

This Barst Fund Award was made possible through a generous, anonymous donation in honor of pediatric PH patient Cordelia.

Summary of Research Project:

Given that more than 140 million people live at high altitude (HA; defined as an altitude of >8200 feet above sea level), high altitude pulmonary hypertension (HAPH) is one of the most common causes for pulmonary hypertension (PH; defined as high blood pressure in the blood vessels of the lungs) worldwide. In common chronic heart and lung diseases seen at sea level, low oxygen (hypoxia) is an important contributor to the development of symptomatic pulmonary hypertension (PH). In contrast, the majority of HA residents adapt to chronic hypoxia and develop asymptomatic high altitude pulmonary hypertension (HAPH). In addition, HA residents display a reversibility of their PH after prolonged residence at sea level. The mechanisms underlying this adaptation and reversibility are unknown. In infants and children at HA, physiologic adaptations in lung growth, gas exchange, and oxygen transport are driven by oxygen-sensitive pathways – most notably the hypoxia-inducible factor (HIF) pathway. In certain populations with long ancestry at HA, these adaptations are driven by genetic mechanisms, however, there is increasing data showing that non-genetic (epigenetic) modifications play a role in the developmental adaptive response to HA. Epigenetic modifications are also increasingly being shown to play a role in the development of pulmonary vascular disease. This is not surprising, given that the growth of the lung and associated vessels are integrally linked. We suspect the adaptive response is due to the exposure of hypoxia in utero, which allows for gradual adaptive mechanisms from the earliest time point in development that can be turned on and off. We hypothesize that in utero exposure to hypoxia triggers gene modifications that affect the pulmonary vasculature and contribute to HAPH adaptation. Using a unique rodent model of in utero hypoxia and postnatal hypoxia, we will study the role of hypoxia-induced epigenetic modifications beginning in embryonic development. We will then evaluate how these modifications are altered when the hypoxic environment is removed. Using DNA sequencing technology to analyze blood and tissue samples, this project will identify DNA methylation processes (which are epigenetic mechanisms to control gene expression) as a modifier of PH development to help determine how HA residents adapt to HAPH. Identifying the epigenetic modifications that allow favorable adaptations to HAPH could provide a mechanism applicable to PH at sea level. A better understanding of the underlying mechanisms would not only lead to new treatment strategies for those with a maladaptive response to HAPH, but would also be applicable to PH developing in lowlanders as a consequence of such common cardiopulmonary diseases as congestive heart failure, chronic obstructive lung disease and obstructive sleep apnea.

Curriculum Vitae

Education/Training

2000-2005: BS in Biological Sciences and BA in Sociology at University of California, Davis in Davis, California
2006-2011: DO in Medicine at A.T. Still University, Kirksville College of Osteopathic Medicine, Kirksville, MO
2011-2014: Resident in Internal Medicine at Indiana University, Indianapolis, IN
2014-present: Fellow in Pulmonary and Critical Care Medicine at Indiana University, Indianapolis, IN

Honors/Awards

2009-2010: Academic Teaching Fellow: Gross Anatomy, Neuroanatomy, and Histology, A.T. Still University, Kirksville College of Osteopathic Medicine, Kirksville, MO
2010: Who’s Who Among Students in American Universities and Colleges, KCOM
2011-2014: Global Health Track Resident, Indiana University School of Medicine
2013: Finalist, Indiana University Department of Medicine Resident Research Competition

Research Support

2016-present
T32 Training Grant
PIs: Stephanie Davis, MD and Mark Geraci, MD
Grant 5T32HL091816-08
Role: Professional development, research design, ongoing coursework in translational research
Goal: Foster development of laboratory skills leading to independent research design and implementation

Selected Publications

Krishnan S, Nephew K, Ivan M, Martínez M, Bonilla F, Cabana C, Llapur CJ, Tepper R. Epigenetic Modifications in Peripheral Blood of Human Infants Born and Raised at High Altitude. Am J Respir Crit Care Med 193;2016:A7841