It is well established that physiologic, imaging, and circulating biomarkers of right ventricular (RV) dysfunction predict adverse outcomes in pulmonary arterial hypertension (PAH), yet our understanding of the genetic, molecular, and cellular determinants of RV failure is nascent. Further, there is a clear clinical need to identify targets directed at preserving and improving RV function in PAH. In this context, our global objectives are to identify and characterize novel molecular determinants and clinical biomarkers of RV function and failure and define both their contribution to disease phenotype and their potential for exploitation as therapeutic targets. Recognizing that cardiopulmonary dysfunction in PAH is linked to pathologic changes in the microvasculature, we rationalized that circulating antagonists of microvascular homeostasis could negatively impact on disease pathogenesis. We have demonstrated that endostatin (ES), a potent inhibitor of angiogenesis (i.e., angiostatic factor), is elevated in PAH, associated with adverse hemodynamic and functional status, and, importantly, w i t h increased mortality in idiopathic and connective tissue disease associated PAH (IPAH and CTD-PAH, respectively). Further, we have identified multiple genetic variants in the gene encoding ES (Col18a1) that are associated with potential altered protein function, protein expression, cardiac function, and outcomes in PAH. This is a five-year grant proposal put forth jointly by a new and an established investigator on the role of Col18a1 / ES on PAH. The objectives of the grant are to further define the relationship between ES and cardiopulmonary structure and function in disease, to further define and characterize the molecular and cellular effects of variants in the gene encoding ES (Col18a), and to provide necessary preclinical data on the impact of ES antagonism as a potential therapeutic target in PAH.

Public Health Relevance

) Our objectives are 1) to identify novel molecular and genetic determinants of disease severity in pulmonary arterial hypertension; 2) to define their mechanism(s) of action; and 3) to develop reagents to target them as new therapies for pulmonary arterial hypertension.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL132153-02
Application #
9398149
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Xiao, Lei
Project Start
2017-01-01
Project End
2020-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205