Autophagy is manifested by degradation of cytoplasmic organelles via a lysosomal pathway, involving rearrangement of intracellular membranes to sequester damaged proteins or organelles within formed membrane vesicles, or autophagosomes. Autophagosomes then fuse with lysosomes where the content is degraded and recycled to become an endogenous source of energy and nutrients. Autophagy has been described in the yeast system for decades;however, we have witnessed the explosion of this field in the mammalian system in recent years. Little is known on the role of autophagy in lung disease, and the role of autophagy in pulmonary hypertension (PH) has not been rigorously explored. We have obtained intriguing preliminary data that human PH and experimental models of PH exhibit marked induction of autophagy. Our laboratory and others have started to unravel the mechanisms and signaling pathways by which carbon monoxide (CO) imparts protective effects in various models of cellular and tissue injury. Importantly, our recent study illustrates that CO can protect against hypoxia or MCT-induced PH in mice and rats, respectively, even after the development of PH suggesting that CO may affect vascular remodeling processes including vascular cell proliferation and apoptosis. Interestingly, we have obtained preliminary data that CO regulates the autophagic process both in cultured vascular cells and in the lung. We hypothesize that autophagy represents an adaptive stress response to protect against PH, and that CO prevents PH via regulating autophagy. Furthermore, we hypothesize that autophagy regulated inflammasomes can potentially serve as diagnostic biomarker in predicting severity of PH. We will test the hypothesis by addressing the following aims:
Specific Aim #1 : To determine the mechanism by which CO-induced autophagy functions to provide cytoprotection in experimental PH Specific Aim 2: To determine the mechanism by which CO dampens the inflammasome pathway in experimental PH Specific Aim #3: To determine whether CO inhibits inflammasome and its regulated cytokines in human PH

Public Health Relevance

Pulmonary arterial hypertension (PAH) is a dreadful disease with no effective therapies. An improved understanding of the pathogenesis of PAH will potentially provide new therapeutic targets. We hope to identify new molecules involved in the autophagy pathway which potentially could represent novel targets for therapy in PAH in the future.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL060234-12A1
Application #
8437918
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Eu, Jerry Pc
Project Start
1999-01-01
Project End
2018-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
12
Fiscal Year
2013
Total Cost
$505,252
Indirect Cost
$205,478
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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