权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

CaMK: Central Regulators of the response to Surgical Sepsis

CaMK：手术败血症反应的中央监管者

基本信息

批准号：
9407788
负责人：
MATTHEW Randall ROSENGART
金额：
$ 33.11万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-03 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9407788
关键词：
Aerobic Affect Aging Aging-Related Process Attenuated Autophagocytosis Bioenergetics Biogenesis Biological Ca(2+)-Calmodulin Dependent Protein Kinase Calcium Cause of Death Cell Respiration Cells Cessation of life Cytoprotection Data Development Elderly Equilibrium Event Failure Family Fostering Functional disorder Health Human In Vitro Infection Injury Investigation Kidney Knowledge Lead Membrane Potentials Mitochondria Molecular Mus Operative Surgical Procedures Organ Organ failure Oxidative Phosphorylation Population Process Proteins Publishing Recovery Regulation Respiration Risk Sampling Secondary to Sepsis Signal Transduction Source Stimulus Stress Tubular formation age related aged attenuation base cell injury clinically relevant high risk population in vivo injured innovation mitochondrial membrane parkin gene/protein public health relevance recruit response septic patients therapy development

项目摘要

DESCRIPTION (provided by applicant): Severe sepsis annually affects over 750,000 people in the US, and more than a third die, primarily due to multiple organ dysfunction (MOD). Though the last decade has seen immense progress in identifying the cellular and molecular mechanisms of MOD, major gaps in our knowledge still remain. Recent studies propose that the initial `organ dysfunction' is due to a regulated induction of a hypometabolic state, the purpose of which is cellular protection. However a delicate balance is required. Insufficient induction, as is observed in aging, may lead to irrecoverable cellular injury and organ dysfunction. On the other hand, with prolonged or overly severe insult, this mechanism of cytoprotection may actually contribute to organ injury. The ability to titrate this response may provide an opportunit to reverse MOD. Our lab seeks to delineate the biological determinants of organ dysfunction during sepsis. We have focused upon calcium (Ca2+) regulation and signaling to show that a family of Ca2+/calmodulin-dependent protein kinases (CaMK) regulate autophagy, a conserved cytoprotective response that enables a cell to recycle cytoplasmic components to adapt to periods of stress. However, Ca2+ signaling is inherently sensitive to the energy status of the cell, and mitochondria, the primary source of aerobic energy, both regulate and are regulated by Ca2+. We now hypothesize that sepsis induces CaMK signaling, which regulates adaptive changes in mitochondrial function to limit cellular injury. These mechanisms are altered during the aging process, which may underlie an increased risk of irreversible organ failure and death. We propose that early during sepsis the CaMK control adaptive changes in mitochondrial function and induce a hypometabolic, hibernating state, the purpose of which is to protect the cell. Severe sepsis perturbs mitochondrial function, leading to mitochondrial depolarization, the inciting event activating the CaMK. These CaMK mark damaged mitochondria for CaMK-dependent mitophagy (i.e. controlled cellular degradation of mitochondria). Concomitantly, the CaMK initiate mitochondrial biogenesis that restores a healthy mitochondrial population, aerobic metabolism, and organ function. Altered expression of these mechanisms occurs during the aging process, which underlies an increased risk of organ dysfunction. In accordance with our hypothesis we propose the following specific aims: Specific Aim 1. To determine that intracellular and mitochondrial Ca2+ signaling activate the family of CaMK to regulate adaptive reductions in mitochondrial respiration and function during sepsis. Specific Aim 2. To determine that mitochondrial Ca2+ signaling selectively targets dysfunctional mitochondria for CaMK-dependent mitophagy and induces CaMK-dependent mitochondrial biogenesis during sepsis. These mechanisms mitigate cellular injury and foster organ recovery. Specific Aim 3. To determine that during aging, a progressive loss in CaMK signaling underlies an attenuation in mitophagy and mitochondrial biogenesis and an increased risk of organ dysfunction during sepsis. These investigations are highly innovative and based upon strong preliminary data. Understanding the mechanisms of a reversible cause of organ dysfunction will enable us to identify high-risk populations (i.e. elderly) and develop therapies to foster recovery even in the setting of established organ dysfunction.