Induction of Inflammation by Mitochondrial Proteins

描述(由申请人提供)：重症监护病房中的大多数死亡与免疫系统调节失调有关。急性疾病，如创伤、胰腺炎、缺血和严重感染，在受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，死亡。最近的研究表明，组织损伤(即细胞死亡)释放出可引起全身炎症的蛋白质。也就是说，HMGB-1，一种核DNA结合蛋白，从受损的细胞中释放出来，进而通过晚期糖基化终产物受体(RAGE)和Toll样受体(TLR)促进单核细胞释放促炎细胞因子。我们实验室的初步数据首次显示线粒体蛋白诱导单核细胞激活。这反映在促炎细胞因子的产生上。有趣的是，线粒体转录因子A(MtTFA)在线粒体中含量丰富，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，可能通过RAGE受体识别激活单核细胞，并能够促进全身炎症反应。特异性目的2：确定线粒体蛋白是否诱导小鼠全身炎症反应。特异性目的3：确定线粒体蛋白，特别是mtTFA是否通过晚期糖基化终产物受体(RAGE)和/或Toll样受体-2和-4激活人外周血单核细胞。这些研究对于更好地理解前馈机制具有重要意义，通过前馈机制，最初的组织损伤引起全身炎症，最终导致器官衰竭和死亡。一旦确定了促进单核/巨噬细胞活化的线粒体蛋白，以及单核细胞活化的机制，就有可能确定新的治疗靶点，以减轻危重病患者未受调节的全身炎症。

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.