Respiration in Sepsis

脓毒症时的呼吸

• 批准号: 8436690
• 负责人: CLAUDE A PIANTADOSI
• 金额: --
• 依托单位: DURHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8436690
• 关键词: 5' -AMP-activated protein kinase; AMP-activated protein kinase kinase; Adenosine Monophosphate; Aging; Agonist; Animal Model; Antibiotics; Apoptosis; Apoptotic; Area; Autophagocytosis; Basic Science; Biogenesis; CREB1 gene; Carbon Monoxide; Caring; Cause of Death; Cell Death; Cell Survival; Cell model; Chemical Warfare; Data; Disease; Energy Metabolism; Event; Failure; Funding; Gene Expression Regulation; Genes; Genetic; Genetic Programming; Goals; Health; Hepatic; Hepatocyte; High Prevalence; Hypoxia; Immune system; Infection; Inflammation; Inflammatory; Lead; Life; Link; Liver; Mediating; Mediator of activation protein; Mitochondria; Mitochondrial DNA; Mitochondrial Proteins; Molecular; Multiple Organ Failure; Mus; Nitric Oxide; Nitric Oxide Synthase; Organ; Oxidation-Reduction; Pathogenesis; Pathway interactions; Phosphorylation; Prevention; Process; Production; Protein Kinase; Proteins; Quality Control; Receptor Activation; Regulation; Respiration; Role; Sentinel; Sepsis; Signal Transduction; Specificity; Standardization; Staphylococcus aureus; Syndrome; Testing; Therapeutic; Thinking; Tissues; Titrations; Toll-like receptors; Transcription factor genes; Transcriptional Regulation; Up-Regulation; Veterans; Work; cell injury; cost; design; high throughput screening; innovation; insight; mortality; novel; nrf1 protein; prevent; programs; public health relevance; respiratory; response; transcription factor

DESCRIPTION (provided by applicant): This VA Merit Review renewal application proposes to study transcriptional regulation of the pro-survival program of mitochondrial biogenesis during experimental S. aureus sepsis. The need for basic research in this area is high due to the high prevalence and cost of sepsis-induced multiple organ dysfunction syndrome (MODS) in older Veterans. This high mortality syndrome is due in part to mitochondrial damage, which is mechanistically poorly understood. Using earlier funding, we discovered that mitochondrial biogenesis in sepsis is activated before energy crisis, while a rescue pathway is delayed involving the adenosine monophosphate (AMP)-activated protein kinase (AMPK) and PGC-1¿ co-activator. New preliminary data links AMPK activation to nitric oxide synthase-2 (NOS2) induction in sepsis, does not require high AMP/ATP, and loss of AMPK activation in nitric oxide synthase-2 (NOS2) deficient mice is accompanied by worsening inflammation. AMPK may serve as an activator of three crucial transcription factors- CREB, NRF-1, and NRF- 2 (GABPA) for mitochondrial biogenesis in sepsis, but NO regulation also induces mitochondrial damage by loss of NO signal specificity and indiscriminate chemical attack on mitochondria by NO species (NOx). We propose that AMPK activation by impending energy failure up-regulates the mitochondrial damage control program in sepsis and if so, NO-independent pharmacological AMPK activation could control excess NO production and mitigate sepsis-induced MODS. We will focus on AMPK in the liver, a sentinel organ, and NOS2 as a quantitative influence on mitochondrial turnover and apoptosis using pharmacological AMPK activation to limit NO-induced mitochondrial damage. Our Specific Aims are: Aim 1: To understand hepatic AMPK activation in sepsis in relation to NOS2 induction, the program of mitochondrial biogenesis, and the prevention of apoptosis. 1A. Define the relationships between AMPK activation and NOx-mediated mtDNA and protein damage, respiratory capacity, high-energy metabolites, and sepsis-induced hepatic cell death using NOS2 gene titration. 1B. Determine if AMPK activation through NO-dependent CREB/NRF-1 activity promotes mitochondrial biogenesis and inhibitory phosphorylation of pro-apoptotic Bad and BNIP3, preventing apoptosis in sepsis. Aim 2: To determine if specific strategies to activate or inhibit AMPK independently of NOS2 regulate hepatic mitochondrial biogenesis and cell survival and lessen NO-dependent cell damage in sepsis. 2A. Determine if the pharmacological activation of AMPK independently of NOS2 promotes mitochondrial biogenesis and/or inhibits apoptosis in sepsis. We will also use high-throughput screening to identify one or more novel selective agonists of AMPK. 2B. Compare NO-dependent and NO-independent AMPK activation for effects on the transcriptional regulation of mitochondrial biogenesis in sepsis using CREB and PGC-1¿ as key readouts. These studies will provide new molecular data on AMPK regulation of mitochondrial biogenesis in sepsis, and on the extent to which NO production is regulatory. Proof-of-concept would lead to rational pharmacological approaches to activate and support mitochondrial biogenesis while minimizing NO-induced collateral damage. Understanding these fundamental regulatory mechanisms is needed to design forward-thinking therapeutic approaches to protect mitochondrial quality control during sepsis.

描述（由申请人提供）：