Stabilizing mitochondria in sepsis

稳定败血症中的线粒体

基本信息

批准号：
10205139
负责人：
Rama K Mallampalli
金额：
$ 47.96万
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 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10205139
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 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 Multiple Organ Failure 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.

败血症是美国非统治重症监护病房中死亡的主要原因。二败血症的病理特征是细胞氧气中的深处缺陷，炎症，两者都可能具有线粒体基础。虽然化粪池受试者有线粒体缺陷，其损伤的分子机制破坏了氧气消费和触发注射尚不清楚。机械平台提案住宅在我们发现独特的线粒体损伤的分子模型上因此，一种新的蛋白质FBXO48可能会破坏线粒体功能以触发通过介导泛素驱动的处置的炎症炎症能量传感器，5'AMP激活的蛋白激酶（AMPK）。通过定位C- FBXO48中存在的末端分子签名，我们设计，合成并测试了A 新型的小分子FBXO48拮抗剂，可稳定线粒体功能和减少了鼠和人类化粪池模型中的感染。因此，在此应用程序中，我们将首先阐明细菌病原体如何通过FBXO48缺少AMPK，从而强调实验性败血症（AIM 1）。我们将专门阐明FBXO48如何将AMPK靶向AMPK 使用完整的体外和体内遗传模型降解。接下来我们将优化药理学设计和测试一种新型的小分子，表现出不同的分子，但化粪池模型中的完全线粒体保护和抗炎特性（目标2）。这些研究将为线粒体损伤提供新的病理生物学模型充当生成优化细胞的小分子调节剂的平台严重重症患者的生物能学和限制炎症。

项目成果

期刊论文数量（28）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Fbxl12 triggers G1 arrest by mediating degradation of calmodulin kinase I.

DOI：
10.1016/j.cellsig.2013.05.012
发表时间：
2013-10
期刊：
Cellular signalling
影响因子：
4.8
作者：
Mallampalli RK;Kaercher L;Snavely C;Pulijala R;Chen BB;Coon T;Zhao J;Agassandian M
通讯作者：
Agassandian M

Targeting F box protein Fbxo3 to control cytokine-driven inflammation.

DOI：
10.4049/jimmunol.1300456
发表时间：
2013-11-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
0
作者：
Mallampalli RK;Coon TA;Glasser JR;Wang C;Dunn SR;Weathington NM;Zhao J;Zou C;Zhao Y;Chen BB
通讯作者：
Chen BB

A combinatorial F box protein directed pathway controls TRAF adaptor stability to regulate inflammation.