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 the past 5 years. Little is known on the role of autophagy in lung diseases. The role of autophagy in PAH has not been explored. We have obtained intriguing preliminary data that human PAH and experimental models of PAH 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 PAH in mice and rats, respectively, even after the development of PAH 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 pulmonary arterial hypertension, and that CO prevents pulmonary arterial hypertension via regulating autophagy. We also hypothesize that the intracellular trafficking of autophagy proteins regulate expression and function of autophagy in PAH. We will test the hypothesis by addressing the following specific aims:
Aim #1 : To determine the mechanism(s) by which autophagy functions to protect against PAH Aim #2: To determine the mechanism(s) by which subcellular trafficking of autophagy proteins Beclin 1 and LC3B regulates autophagy in PAH Aim #3: To determine the mechanism(s) by which CO induced autophagy confers protection against PAH
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.
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