Each year, nearly 2 million people in the US require hospitalization for sepsis, and 1 in 3 will die. Guidelines standardizing the care of sepsis clearly work, but not for everyone. Many patients receive optimal sepsis care, and yet, they still die. Those patients that do survive the initial infection and are discharged from the hospital continue to experience an elevated risk of long-term (>2 years later) death that is as high as the long-term mortality after hospitalization for heart failure or stroke. Clearly, these patients are not ?healed?. Our lab seeks to identify the biological causes of cellular dysfunction during and after sepsis. We build upon our paradigm that members of a family of Ca2+ /calmodulin-dependent protein kinases (CaMK) function as rheostats to finely balance Ca2+ regulation and ATP generation by adaptively altering mitochondrial dynamics in the cellular response to stress. We propose that during sepsis mitochondria undergo evolutionarily conserved and adaptive alterations in their structure and function that serve the purpose of cell survival, but underlie a persistent organ dysfunction, resistant to contemporary sepsis therapies. These mechanisms durably restructure the complex machinery that regulates mitochondrial Ca2+ homeostasis, and in doing so, fundamentally alter future Ca2+ signaling and the phenotype of the cell; this imparts an elevated risk of long-term death for those who survive. These data underscore the mechanistic vantage point at which the CaMK reside in balancing the energetic needs of the cell and mitochondrial Ca2+ homeostasis with cell death and survival. In accordance with our hypothesis we propose the following specific aims:
Aim 1. To determine that the CaMK-dependent mechanisms regulating fission, fusion and mitophagy restructure the molecular machinery governing mitochondrial Ca2+ homeostasis in both immune and non-immune tissues. This fundamentally alters subsequent Ca2+/CaMK signaling and cellular oxidative metabolism.
Aim 2. To characterize the contribution of individual components of the MCU complex to mitochondrial Ca2+ homeostasis and the cytosolic Ca2+ transients (Caic) that mediate CaMK-dependent alterations in mitochondrial dynamics in the immune and nonimmune cells. The current mechanistic paradigm of sepsis is incomplete. The data derived from the conduct of this proposal carry the potential to fundamentally shift our current understanding of the biology of sepsis and facilitate the development of novel ?metabolic? resuscitation and mitochondrial reprogramming techniques that compliment contemporary resuscitation strategies to improve both short- and long-term survival.
An explanation is needed as to why organ failure still develops or fails to resolve and death ensues in patients for whom we have expeditiously delivered medical and surgical care. And why patients continue to die at an elevated rate even after we have ?healed? them from a single episode of sepsis. Our characterization of the biological mechanisms through which adaptive alterations of mitochondrial dynamics preserve cell survival seeks to fundamentally shift our understanding of sepsis biology and answer these questions. In doing so, it will enable the development of novel ?metabolic? resuscitation strategies that improve short-term outcomes. The hypothesis that the mitochondrion restructures itself as an adaptive mechanism to ?learn? from the past is innovative and provides an explanation for the elevated risk of long-term death observed in survivors. It is hoped that this knowledge will enable a personalized approach to realign these biological trajectories to a more adaptive, healthy phenotype and improve long-term outcomes.
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