This is an application for a career development award to establish the PI with advanced training in molecular physiology in preparation for a career as an independent investigator in the area of sepsis-related organ failure. The PI will investigate the role of the mitochondrial DNA repair (mDNA) enzyme, OGG1 and nuclear coactivators, PGC-11 and its family members, in mtDNA maintenance and biogenesis in a murine Staphylococcus sepsis model. MtDNA is a critical target of oxidative and nitrosative damage from cytokine and chemokine release, and mitochondrial biogenesis is one of the critical repair mechanisms. My overall working hypothesis is that the maintenance of adequate mitochondrial function in sepsis requires nuclear coordination of an integrated program of mtDNA repair and mtDNA replication in order to ensure fidelity of mtDNA transcription and for mitochondrial biogenesis given that sepsis leads to mtDNA damage by reactive oxygen species and reactive nitrogen species. If this mtDNA damage from sepsis exceeds the cell's ability to repair damaged mtDNA, fewer mitochondrial genomes will be available for transcription;this inflammatory insult will decrease the cells'capacity for oxidative phosphorylation. The cell either accommodates to this change in functional mtDNA equilibrium through mitochondrial biogenesis, or the cell will undergo death by either necrosis or apoptosis. Therefore, I hypothesize that enhanced mtDNA repair in sepsis is a prerequisite for mitochondrial biogenesis to avert the energy failure that would lead to organ injury. This hypothesis will be tested with the following specific Aims:
Specific Aim 1 : Understand the role of OGG1 in maintenance of mtDNA copy number during Staph aureus sepsis in mice.
Specific Aim 2 : Identify the critical nuclear co-activator for NRF-1-induced Ogg1 gene expression in gram positive sepsis and sepsis-related inflammation.
Specific Aim 3 : Understand the importance of the AMP-kinase pathway activation in sepsis as it relates to nuclear co-activator function and mtDNA repair enzyme induction. The completion of these Aims will improve our understanding of the role of mtDNA damage and repair in severe sepsis and in protection from organ failure that would lend itself to the development of novel prognostic and therapeutic strategies for host protection.
Sepsis is the 10th leading cause of mortality in the United States. Current strategies to treat sepsis beyond supportive care and antibiotics are limited. Understanding the pathophysiologic processes that lead to sepsis- induced organ dysfunction will ultimately lead to new therapeutic pathways.
