Stabilizing mitochondria in sepsis

败血症是美国非冠状动脉重症监护病房的主要死亡原因。两 脓毒症的特征是细胞氧提取的严重缺陷， 炎症，两者都可能有线粒体基础。尽管败血症患者 线粒体缺陷，破坏氧的损伤的分子机制 消耗和引发炎症仍不清楚。这个机械平台 我们的建议在于我们发现了一个独特的线粒体损伤的分子模型 一种新的蛋白质Fbxo 48，可以有效地破坏线粒体功能， 炎症通过介导泛素驱动的处理一个关键的细胞保护，抗- 炎症能量传感器5′-AMP活化蛋白激酶（AMPK）。以C为目标- Fbxo 48中存在的末端分子特征，我们设计、合成并测试了一种 一类新的小分子Fbxo 48拮抗剂，其稳定线粒体功能， 减少小鼠和人类脓毒症模型中的炎症。因此，在本申请中，我们将 首先阐明细菌病原体如何通过Fbxo 48消耗AMPK，从而加重 实验性脓毒症（Aim 1）。我们将具体阐明Fbxo 48如何靶向AMPK， 使用互补的体外和体内遗传模型进行降解。接下来我们将优化 药理学设计和测试了一种新的小分子， 在脓毒症模型中的补充性尿道保护和抗炎特性 (Aim 2）。这些研究将提供一种新的线粒体损伤的病理生物学模型， 作为产生小分子调节剂的平台， 生物能量学和限制严重危重病受试者的炎症。

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.