Sepsis is the leading cause of death in US noncoronary intensive care units. Two pathognomonic features of sepsis are a profound defect in cellular oxygen extraction and inflammation, both of which may have a mitochondrial basis. Although septic subjects have mitochondrial defects, the molecular mechanisms underlying their injury that disrupt oxygen consumption and trigger inflammation remain unclear. The mechanistic platform 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 ubiquitin-driven disposal 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 class of small molecule Fbxo48 antagonists which stabilize mitochondrial function and reduces inflammation in murine and human septic models. Hence, in this application we will first elucidate how bacterial pathogens deplete AMPK through Fbxo48, thereby accentuating experimental sepsis (Aim 1). We will specifically elucidate how Fbxo48 targets AMPK 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 mitochondrial-protective and anti-inflammatory properties in septic models (Aim 2). These studies will provide a new pathobiologic model of mitochondrial 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.
Sepsis 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 organ 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 septic subjects that led us to develop a novel drug that reduces the oxygen defect and inflammation. This discovery fulfills an unmet need in this critical illness.
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