Induction of Inflammation by Mitochondrial Proteins

描述（由申请人提供）：重症监护室的大多数死亡与免疫系统失调有关。 急性疾病，如创伤、胰腺炎、缺血和严重感染，在损伤或感染部位引起强烈的局部炎症反应，随后促进全身炎症反应，在许多情况下导致死亡。最近的研究表明，组织损伤（即，细胞死亡）释放可诱导全身炎症的蛋白质。也就是说，HMGB-1，一种核DNA结合蛋白，从受损细胞中释放，进而促进促炎细胞因子通过晚期糖基化终产物受体（AGEs）和Toll样受体（TLR）从单核细胞中释放。我们实验室的初步数据首次表明，线粒体蛋白诱导单核细胞活化。如促炎细胞因子产生所反映的。有趣的是，线粒体转录因子A（mtTFA）在线粒体中丰富，并且在功能和结构上与HMGB-1相似。因此，我们假设，线粒体蛋白，特别是mtTFA，可以激活单核细胞通过α受体识别，并能够促进全身炎症反应，提出了以下目标：具体目的1：鉴定线粒体蛋白，诱导细胞因子的释放从单核细胞在体外。具体目的2：确定线粒体蛋白是否诱导小鼠的全身炎症反应。具体目标3：确定线粒体蛋白，特别是mtTFA，是否通过晚期糖基化终产物（AGEs）受体和/或Toll样受体-2和-4激活人外周血单核细胞。这些研究对更好地理解前馈机制具有重要意义，通过该机制，初始组织损伤引起全身炎症，最终导致器官衰竭和死亡。一旦确定了负责促进单核细胞/巨噬细胞活化的线粒体蛋白和单核细胞活化的机制，就可以确定新的治疗靶点，以减轻重症患者中不受调节的全身性炎症。

DESCRIPTION (provided by applicant): The majority of fatalities in intensive care units are related to dysregulation of the immune system. Acute illnesses, such as trauma, pancreatitis, ischemia and severe infections, evoke an intense local inflammatory response at the site of injury or infection that subsequently promotes a systemic inflammation response and in many cases, death. Recent investigations have shown that tissue damage (i.e., cell death) liberates proteins that can induce systemic inflammation. Namely, HMGB-1, a nuclear DNA binding protein, is released from damaged cells, promoting, in turn, the release of pro-inflammatory cytokines from monocytes via receptors for advanced glycation end products (RAGE) and Toll-like receptors (TLR). Preliminary data from our laboratories shows for the first time that mitochondrial proteins induce the activation of monocytes. as reflected by pro-inflammatory cytokine production. Interestingly, mitochondrial transcription factor A (mtTFA) is abundant in mitochondria, and is functionally and structurally similar to HMGB-1. Thus, we hypothesize that mitochondrial proteins, particularly mtTFA, may activate monocytes via RAGE receptor recognition and are capable of promoting a systemic inflammation response The following aims are proposed: SPECIFIC AIM 1: To identify mitochondrial proteins which induce the release of cytokines from monocytes in vitro. SPECIFIC AIM 2: To determine if mitochondrial proteins induce a systemic inflammatory response in mice. SPECIFIC AIM 3: To determine if mitochondrial proteins, particularly mtTFA, activate human peripheral blood monocytes via receptors for advanced glycation end products (RAGE) and/or Toll-like receptors -2 and -4. These investigations have important implications toward better understanding the feed-forward mechanisms through which initial tissue injury begets systemic inflammation, culminating in organ failure and death. Once the mitochondrial proteins responsible for the promotion of monocyte/macrophage activation, and the mechanism of monocyte activation has been identified, new therapeutic targets may be identified to attenuate unregulated systemic inflammation in critically ill patients.