Targeting F-box protein 048 in acute lung injury

急性肺损伤（Acute lung injury， ALI）是一种常见于退伍军人的毁灭性疾病

Acute lung injury (ALI) is a devastating disorder among Veterans commonly occurring after sepsis or severe pneumonia. Two key manifestations of ALI are a fundamental inability to extract oxygen and inflammation, both of which may have a mitochondrial basis. Although ALI subjects have mitochondrial defects, the molecular mechanisms underlying their injury that disrupt oxygen consumption and trigger inflammation remain unclear. The mechanistic basis of this proposal resides on our discovery of a unique molecular model of mitochondrial injury whereby a new protein, Fbxo48, potently disrupts mitochondrial function to trigger inflammation by mediating degradation of a crucial cytoprotective, anti-inflammatory energy sensor, 5′-AMP-activated protein kinase (AMPK). By targeting the C-terminal molecular signature present in Fbxo48, we designed, synthesized, and tested a novel small molecule, BC-1618, that stabilizes AMPK levels, preserves mitochondrial function, and reduces inflammation in murine and human ALI models. Thus, in this application we will first elucidate how a common pathogen, S. aureus, depletes AMPK through Fbxo48, thereby accentuating experimental ALI (Aim 1). We will specifically elucidate how Fbxo48 targets AMPK for its degradation using complementary in vitro and in vivo genetic models, including CRISPR/Cas9 Fbxo48 knockout mice. Next we will examine the pharmacokinetic and pharmacodynamics properties of BC-1618 focusing on its mitochondrial-protective and anti- inflammatory properties in ALI models (Aim 2). A unique approach in this application is execution of small molecule testing in an ex vivo human lung perfusion system. These studies will provide a new pathobiologic model of mitochondrial injury that will serve as a platform for presenting the first-in-class dual acting small molecule modulator that optimizes cellular bioenergetics and limits inflammation in subjects with severe critical illness.