Stabilizing mitochondria in sepsis

脓毒症是美国非冠脉重症监护病房的主要死亡原因。二 脓毒症的病理特征是细胞氧摄取和细胞功能的严重缺陷。 炎症，两者都可能有线粒体的基础。尽管败血症患者有 线粒体缺陷，破坏氧气的损伤的分子机制 消费和引发炎症的原因仍不清楚。这是一种机械平台 提案基于我们发现了线粒体损伤的独特分子模型 因此，一种名为Fbxo48的新蛋白质可以有效地破坏线粒体功能，从而触发 炎症通过介导泛素驱动的至关重要的细胞保护性、抗炎性 炎性能量感受器，5‘-AMP激活的蛋白激酶(AMPK)。通过瞄准C- Fbxo48中存在的末端分子签名，我们设计、合成并测试了一种 新型小分子Fbxo48拮抗剂，稳定线粒体功能和 减少小鼠和人类败血症模型的炎症。因此，在此应用程序中，我们将 首先阐明细菌如何通过Fbxo48消耗AMPK，从而加重 实验性脓毒症(目标1)。我们将具体说明Fbxo48如何针对AMPK进行其 利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 药理设计和测试一种新的小分子，表现出独特的，但 脓毒症模型中线粒体的互补保护和抗炎作用 (目标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 作为生成优化细胞的小分子调制器的平台 生物能量学和限制严重危重疾病患者的炎症。

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.