Acute lung injury (ALI) can be a devastating disorder secondary to pneumonia or sepsis. Two hallmarks of ALI are (1) profound alveolar inflammation, and (2) defects in cellular oxygen extraction, both of which may have a mitochondrial basis. Although ALI subjects have mitochondrial defects, the molecular mechanisms by which impairment of these organelles trigger inflammation and disrupt oxygen consumption remain unclear. Here we discovered in preliminary studies that in ALI models there is a deficiency of a crucial cytoprotective, anti-inflammatory mitochondrial homeostat, Parkin, through its elimination by a relatively new E3 ligase protein, Fbxo7. By targeting the FP molecular signature present in Fbxo7, we designed and tested a novel small molecule inhibitor, BC1464, which stabilizes mitochondrial function and reduces inflammation in murine and human ALI models. Hence, in this application we will first elucidate how bacterial pathogens deplete Parkin through Fbxo7, thereby accentuating experimental ALI (Aim 1). We will specifically elucidate how Fbxo7 targets Parkin for its degradation using complementary in vitro and in vivo genetic models. Next, we will optimize the pharmacologic design and test a novel small molecule that exhibits distinct, and yet complementary anti-inflammatory and mitochondrial-protective properties in ALI models including an isolated human perfused lung system (Aim 2). These studies will provide a new pathobiologic model of lung injury that will serve as a platform for generating small molecule modulators that optimize cellular bioenergetics and limit inflammation in subjects with severe critical illness.
Acute lung injury (ALI) is a major cause of death in the US and evidence suggests that patients die from overwhelming lack of ability to use oxygen coupled with inflammation, making people prone to severe lung injury. The oxygen defect may be due to damage to energy-producing mitochondria in cells. We have discovered a new model that may explain these abnormalities in ALI subjects that led us to develop a novel drug that reduces the oxygen defect and inflammation. This discovery fulfills an unmet need in ALI therapy.
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