Microvesicular inflammasomes: role in sepsis

 描述（由申请人提供）：仅在美国，每年就有超过500，000人发生败血症，导致175，000人死亡。先天宿主反应的复杂性及其与确定对病原体和危险信号的最终反应的相关性与脓毒症反应特别相关。近年来，细胞损伤和凋亡被认为是脓毒症免疫应答的关键调节因子。虽然对脓毒症中细胞损伤和死亡的发病机制了解很多，但我们的知识中存在一些空白;因此，目前没有有效的药物治疗。在这种情况下，称为半胱天冬酶的酶是完成凋亡程序所必需的。吞噬细胞，特别是单核细胞/巨噬细胞，被认为是肺中炎症和免疫反应的主要组分，并且是胱天蛋白酶，特别是胱天蛋白酶-1的丰富储存库。caspase-1的功能已被认为超出了IL-10和IL-18的加工和激活，包括调节NF-κ B和诱导细胞凋亡。目前的建议旨在扩大我们最近的观察，即微泡半胱天冬酶-1可以从单核吞噬细胞释放，对靶细胞有远距离的影响。目前的建议旨在调查一种新的假说，凋亡酶，半胱天冬酶-1，封装在循环囊泡，细胞损伤和凋亡。这一建议提供了一个非常需要的努力和框架，以研究脓毒症患者脾脏和外周血淋巴细胞耗竭的机制知之甚少，提高我们对细胞损伤的分子机制的理解，并提供新的治疗机会，以阻止脓毒症患者的器官破坏。因此，为了确定 本研究的主要目的是：1）明确caspase-1在炎症小体激活过程中对脓毒症的调控作用。2)阐明严重脓毒症时单核吞噬细胞释放的caspase-1调节淋巴细胞存活和功能的机制; 3）确定caspase-1介导的淋巴细胞丢失是否预测脓毒症患者的临床结局。这项工作的成功完成将揭示微泡caspase-1和炎性体信号传导的关键组分，增强我们对细胞损伤潜在分子机制的理解，并提供新的治疗机会来阻止脓毒症患者的器官破坏。

 DESCRIPTION (provided by applicant): Over 500,000 people develop sepsis annually in United States alone, resulting in 175,000 fatalities. The complexity of the innate host response and its relevance to determining the ultimate response to pathogens and danger signals is particularly relevant to the sepsis response. Recently, cell injury and apoptosis has been described as key regulator of immune responses in sepsis. Although much is known about the pathogenesis of cell injury and death in sepsis, there are several gaps in our knowledge; as a result of which there is currently no effective pharmacologic therapy. In this context, enzymes known as caspases are essential for completion of the apoptotic program. Phagocytes, in particular monocyte/macrophages, are recognized as major components of inflammatory and immunologic reactions in the lung and are rich reservoirs of caspases, especially caspase-1. The function of caspase-1 has recently been recognized to extend beyond the processing and activation of IL-1ß and IL-18 to include regulation of NF-kB and induction of apoptosis. The present proposal seeks to expand upon our recent observation that microvesicular caspase-1 can be released from mononuclear phagocytes to have distant effects on target cells. The present proposal seeks to investigate a novel hypothesis that links the apoptotic enzyme, caspase-1, encapsulated in circulatory vesicles, to cell injury and apoptosis. This proposal provides a much needed effort and framework to study the poorly understood mechanism of splenic and peripheral blood lymphocyte depletion in septic patients, enhance our understanding of the molecular mechanisms underlying the cell injury and provide new therapeutic opportunities to halt the organ destruction in septic patients. Therefore, to determine the specifics of this novel pathway, we propose the following specific aims: 1) To identify the role of caspase-1 in regulating sepsis response via inflammasome activation events., 2) To elucidate the mechanisms by which caspase-1 released from mononuclear phagocyte regulates lymphocyte survival and function in severe sepsis and 3) To determine if caspase-1 mediated lymphocyte loss predicts clinic outcomes in septic patients This proposal provides an opportunity to examine the role of caspase-1 in the complex biology of cell interactions and apoptosis. Successful completion of this work will uncover critical components of microvesicular caspase-1 and inflammasome signaling enhance our understanding of the molecular mechanisms underlying the cell injury and provide new therapeutic opportunities to halt the organ destruction in septic patients.