Stabilizing mitochondria in sepsis

稳定败血症中的线粒体

基本信息

批准号：
9726032
负责人：
Rama K Mallampalli
金额：
$ 47.97万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-11-29 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9726032
关键词：
5&apos -AMP-activated protein kinase Acute Anti-Inflammatory Agents Apoptosis Attenuated Autophagocytosis Behavior Bioenergetics Biological C-terminal Caring Cartoons Cause of Death Cells Cellular biology Clinical Trials Coupled Critical Illness Data Defect Disease Edema Exhibits Failure Foundations Genetic Models Homeostasis Human Immune response Impairment In Vitro Inflammation Inflammatory Inflammatory Response Injury Intensive Care Units Invaded Maintenance Mediating Metabolic Mitochondria Modeling Molecular Molecular Profiling Mus Muscle Oxygen Oxygen Consumption Pathogenesis Patients Pattern Pharmacology Phosphorylation Phosphotransferases Play Property Protein Kinase Proteins Reactive Oxygen Species Regulation Respiratory Diaphragm Role Sepsis Severities System Testing Therapeutic Ubiquitin Work base cytokine design improved in silico in vivo inhibitor/antagonist mitochondrial dysfunction model design molecular modeling novel novel therapeutics organ injury pathogenic bacteria pathogenic microbe pre-clinical preservation protein degradation response restoration sensor septic small molecule small molecule therapeutics tissue injury tissue oxygenation ubiquitin-protein ligase

项目摘要

Sepsis is the leading cause of death in US noncoronary intensive care units. Two pathognomonic features of sepsis are a profound defect in cellular oxygen extraction and inflammation, both of which may have a mitochondrial basis. Although septic subjects have mitochondrial defects, the molecular mechanisms underlying their injury that disrupt oxygen consumption and trigger inflammation remain unclear. The mechanistic platform of this proposal resides on our discovery of a unique molecular model of mitochondrial injury whereby a new protein, Fbxo48, potently disrupts mitochondrial function to trigger inflammation by mediating ubiquitin-driven disposal of a crucial cytoprotective, anti- inflammatory energy sensor, 5′-AMP-activated protein kinase (AMPK). By targeting the C- terminal molecular signature present in Fbxo48, we designed, synthesized, and tested a novel class of small molecule Fbxo48 antagonists which stabilize mitochondrial function and reduces inflammation in murine and human septic models. Hence, in this application we will first elucidate how bacterial pathogens deplete AMPK through Fbxo48, thereby accentuating experimental sepsis (Aim 1). We will specifically elucidate how Fbxo48 targets AMPK for its degradation using complementary in vitro and in vivo genetic models. Next we will optimize the pharmacologic design and test a novel small molecule that exhibits distinct, and yet complementary mitochondrial-protective and anti-inflammatory properties in septic models (Aim 2). These studies will provide a new pathobiologic model of mitochondrial injury that will serve as a platform for generating small molecule modulators that optimize cellular bioenergetics and limit inflammation in subjects with severe critical illness.

脓毒症是美国非冠心病重症监护病房的主要原因。脓毒症的病理特征是细胞氧提取和代谢方面的严重缺陷。炎症，这两者都可能有线粒体基础，尽管脓毒症受试者有。线粒体缺陷，其损伤背后破坏氧气的分子机制消耗和引发炎症的机制尚不清楚。该提案基于我们发现了一种独特的线粒体损伤分子模型因此，一种新的蛋白质 Fbxo48 可以有效破坏线粒体功能，从而触发通过介导泛素驱动的关键细胞保护、抗- 炎症能量传感器，5'-AMP 激活蛋白激酶 (AMPK) 通过靶向 C-。 Fbxo48 中存在的末端分子特征，我们设计、合成并测试了新型小分子 Fbxo48 拮抗剂，可稳定线粒体功能因此，在本应用中，我们将减少小鼠和人类脓毒症模型中的炎症。首先阐明细菌病原体如何通过 Fbxo48 消耗 AMPK，从而强调实验性脓毒症（目标 1）我们将具体阐明 Fbxo48 如何靶向 AMPK。接下来我们将使用互补的体外和体内遗传模型进行降解。药理学设计和测试一种新颖的小分子，该分子表现出独特的但脓毒症模型中线粒体保护和抗炎特性的互补（目标 2）这些研究将提供一种新的线粒体损伤病理生物学模型。作为生成优化细胞的小分子调节剂的平台生物能学并限制患有严重危重疾病的受试者的炎症。