Role of CHOP During Sepsis

在过去的几年里，我们一直在研究C/EBP同源蛋白(CHOP)的作用 在败血症的发病机制中起重要作用。这种转录因子是内质网的中介。 (呃)应激反应。内质网对细胞存活至关重要，因为这是后 新合成蛋白质的翻译修饰、折叠和组装。许多行 有证据表明，炎症反应和内质网应激反应之间存在相互作用， 而后者被认为与几种重要的人类病理有关，比如肥胖， 2型糖尿病、动脉粥样硬化和神经退行性疾病。在某些情况下， 未折叠蛋白的积累导致内质网应激。这种应激反应被称为“展开的-- 蛋白质反应“(UPR)保护细胞免受各种伤害，对动态平衡很重要。 CHOP是内质网应激反应的重要介质之一，被认为是一种促进内质网应激反应的因子。 细胞凋亡调节剂。然而，最近的证据表明，CHOP也可能起到重要的作用 在炎症过程中发挥作用，提示它不仅参与了细胞凋亡。 使用CHOP KO小鼠，我们第一次显示这些小鼠表现出显著的 与WT小鼠相比，多菌败血症或内毒素血症后的存活率增加。这个 这些小鼠的炎症反应和脾细胞凋亡显著减少，而 血液和腹膜腔细菌清除量增加。因此，我们的研究表明 这种转录因子在决定生存中扮演着一个关键而未被承认的角色。这些新的 令人兴奋的发现将我们带到了我们的假设，即CHOP是一个新的决定因素 脓毒症期间的存活这一探索性应用的总体目标是获得初步的 CHOP缺失导致大鼠存活率显著增加的机制洞察(S) 老鼠。我们证明CHOP与生存直接相关，尽管机制尚不清楚。 在此应用程序中，我们将研究CHOP在目标1)白细胞招募和 贩运，目标2)巨噬细胞的极化和功能，以及目标3)脾边缘地带 在生存中扮演的角色。 这些研究将大大增加我们对 脓毒症时参与先天免疫反应的机制。因为严重的败血症和 感染性休克仍然是重症监护病房的主要死亡原因，每年有超过21万人死亡 美国的死亡人数，识别新的分子靶点以提高存活率 如果成功，这种综合症可能会对公众健康产生重大影响。

In the past years we have been investigating the role of C/EBP homologous protein (CHOP) in the pathogenesis of sepsis. This transcription factor is a mediator of the endoplasmic reticulum (ER) stress response. The ER is crucial for cell survival because this is the site of post- translational modifications, folding, and assembly of newly synthesized proteins. Many lines of evidence suggest a cross-talk between the inflammatory response and the ER-stress response, and the latter has been implicated in several, important human pathologies such as obesity, diabetes type 2, atherosclerosis and neurodegenerative disorders. In some instances, accumulation of unfolded proteins leads to ER stress. This stress response, called the “unfolded- protein response” (UPR) protects cells from various insults and is important to homeostasis. CHOP is one of the important mediators of the ER stress response and known to be a pro- apoptotic modulator. However, recent evidence indicates that CHOP may also play an important role during inflammation, suggesting that it is not only involved in apoptosis. Using CHOP KO mice we show for the first time that these mice display a significantly increased survival after polymicrobial sepsis or endotoxemia compared to WT mice. The inflammatory response, and apoptosis in the spleen in these mice, is highly reduced while bacterial clearance in the blood and peritoneum cavity augmented. Thus, our study demonstrated a crucial and unacknowledged role for this transcription factor in dictating survival. These new and exciting findings brought us to our hypothesis that CHOP is a novel determinant of survival during sepsis The overall goal of this exploratory application is to gain preliminary insight on the mechanism(s) by which Chop deletion leads to a significant increase in survival in mice. We show that CHOP is directly linked to survival, although the mechanisms are unknown. In this application we will investigate the role that CHOP plays in aim #1) leukocyte recruiting and trafficking, aim #2) macrophages polarization and function, and aim #3) splenic marginal zone role in survival. These studies will significantly increase our knowledge and understanding of the mechanisms involved in the innate immune response during sepsis. Since severe sepsis and septic shock remain a leading cause of death in the intensive care unit, with over 210,000 annual deaths in the United States, identification of new molecular targets to improve survival from this syndrome, if successful, could have a major public health benefit.