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

Mitochondrial injury and repair in sepsis-induced acute kidney injury

脓毒症引起的急性肾损伤中的线粒体损伤和修复

基本信息

批准号：
8792229
负责人：
LEE A MACMILLAN-CROW
金额：
$ 27.52万
依托单位：
UNIV OF ARKANSAS FOR MED SCIS
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-02-01 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8792229
关键词：
Acute Renal Failure with Renal Papillary Necrosis Antioxidants Area Biogenesis Biological Markers Blood capillaries Cells Cessation of life Chronic Complex Data Dithiothreitol Dose Electron Microscopy Epithelial Epithelial Cells Epithelium Event Excision Functional disorder Gatekeeping Generations Glomerular Filtration Rate Health Healthcare Human Individual Infection Inflammatory Response Injury Kidney Kidney Failure Laboratories Ligation Manganese Superoxide Dismutase Measures Mediating Medical Microcirculation Mitochondria Mitochondrial DNA Mitochondrial Proteins Modeling Molecular Monitor Mus NADH dehydrogenase (ubiquinone)Oxidants Patients Peroxisome Proliferator-Activated Receptors Phase Proteins Public Health Puncture procedure Recovery Reducing Agents Renal Tissue Renal function Reporting Research Resolution Respiratory Chain Risk Factors Sepsis Stimulation of Cell Proliferation Superoxides Supportive care Symptoms Testing Therapeutic Time Tubular formation Vent Video Microscopy base capillary care burden clinically relevant defined contribution effective therapy improved improved functioning in vitro Model in vivo injury and repair innovation kidney repair microbial mitochondrial dysfunction mitoquinone mortality mouse model neglect novel novel strategies prevent protein expression renal epithelium repaired respiratory septic

项目摘要

DESCRIPTION (provided by applicant): Sepsis is a serious medical condition characterized by a severe systemic inflammatory response caused by a microbial infection. In the US, sepsis causes ~ 215,000 deaths annually and a healthcare burden of ~ $17 billion. As many as 50% of septic patients develop acute kidney injury (AKI) and this increases mortality from 25% to 75%. Currently, there are no effective therapies to treat sepsis and clinicians must rely only on supportive care usually initiated after the presence of symptoms. Our laboratories recently reported that renal microcirculatory failure and renal mitochondrial superoxide (O2-) generation occur in the mouse by 4h after induction of sepsis, and these events precede the decline in renal function. Importantly, agents that scavenge oxidants allowed the microcirculation to recover and prevented renal injury. Now we have data showing that activities in the kidney of the major mitochondrial O2- scavenger, manganese superoxide dismutase (MnSOD) is decreased ~50% by 4h post sepsis and mitochondrial complex II/III is decreased ~30% at 6h. Also, sepsis induced mitochondrial damage stimulates mitophagy (safe removal of mitochondria); however, mitochondrial biogenesis (mitogenesis) is impaired. Based on these data, we hypothesize that during sepsis increased mitochondrial superoxide is a result of both the loss of MnSOD activity and reduced Complex II/III activity. The resulting mitochondrial damage triggers mitophagy but excessive superoxide dampens functional mitochondrial biogenesis. Consequently, agents, which reduce mitochondrial superoxide will allow for functional mitogenesis and improve sepsis-induced AKI. Three Specific Aims using both the in vivo CLP model as well as a primary cell in vitro model will test this hypothesis. Aim 1 will establish the temporal relationships between MnSOD inactivation and respiratory chain dysfunction (damage phase) to mitophagy and mitogenesis (attempted recovery phase) during sepsis in mice. Aim 2 will investigate the molecular mechanisms that inactivate renal epithelial MnSOD during sepsis. Finally, studies in Aim 3 will evaluate the therapeutic potential of mitochondria-targeted antioxidants to reduce renal mitochondrial dysfunction and promote repair during sepsis using a clinically relevant dosing paradigm. The proposal is significant and innovative from not just a public health perspective but also from a pharmacological perspective. It will provide the scientific basis for targeting repair, a neglected area of sepsis research and critically important in the kidney because even mild AKI is recognized as a significant risk factor for chronic AKI.

描述（由申请人提供）：