Pulmonary arterial hypertension (PAH) is a lethal disease characterized by endothelial cell dysfunction and progressive inward vascular growth that leads to hypertension and ultimately right heart failure. Currently approved PAH therapies focus on dilating structurally-abnormal vessels for improved quality of life, however lung transplantation remains the only cure for advanced disease. PAH is associated with metabolic defects as patients demonstrate insulin resistance and impaired intracellular glucose metabolism. Here we seek to identify aberrant metabolic pathways associated with PAH as opportunities for therapeutic intervention, by profiling the metabolome of endothelial cells that have been implicated as the site of disease origin. In addition, we seek to understand whether an altered metabolome or post-translational modification status underlies the aberrant PPAR?-protein complexes associated with PAH. To investigate we will immunoprecipitate PPAR? from endothelial cells and apply metabolomic and proteomic analysis to identify bound small molecules and covalent protein modifications. Altered metabolites and aberrant metabolic pathways associated with PAH will be validated with chemical and genetic tools in cellular assays. The overarching goal of this proposal is to characterize the molecular underpinnings of PAH as a means to identify novel therapeutic strategies.

Public Health Relevance

Pulmonary arterial hypertension (PAH) is a lethal disease characterized by progressive inward vascular growth that leads to hypertension and ultimately right heart failure. The proposed work seeks to compare PAH patient lungs with healthy donors to identify dysregulated metabolic pathways associated with the disease as opportunities for therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32HL132452-02
Application #
9341950
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Colombini-Hatch, Sandra
Project Start
2016-08-01
Project End
2019-07-31
Budget Start
2017-08-01
Budget End
2018-07-31
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Stanford University
Department
Genetics
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94304