Mechanisms of Intestinal Integrity in Sepsis and Shock

脓毒症是美国危重患者死亡的主要原因， 每年有37万人死于这种疾病。除了抗生素，败血症的治疗是非特异性的， 一旦抗生素和支持性治疗失败，就没有批准的治疗方法可用。肠道已经很长时间 被定性为多器官功能障碍综合征的运动障碍。我们已经花了三个前 研究肠道完整性机制的资金周期（首先是细胞凋亡，然后是增殖、迁移和 渗透性）。这种更新是我们如何看待败血症肠道演变的合乎逻辑的下一步。我们 建议分析肠上皮细胞，免疫系统和微生物组，无论是在隔离，也在 一个区室的改变如何影响其他区室的背景，因为我们假设这种策略将产生 只有使用这种更全面的方法才能获得的见解。该提案的第一个目标是 了解免疫系统和微生物组改变缺乏免疫系统的小鼠存活的机制。 紧密连接相关蛋白连接粘附分子-A（JAM-A），其在 渗透性、菌血症和脓毒症后的存活率。这将使用小鼠与 JAM-A的全身和精氨酸特异性缺失以及具有受控改变的小鼠， 内源性细菌此外，肠通透性由两个紧密连接依赖性途径控制 和紧密连接非依赖性通路。每一种都允许不同大小的分子离开肠腔进入 腔外环境。通过遗传改变这些渗透性途径中的每一个（泄漏，孔隙和渗透性）， 不受限制的途径分别），研究将确定每一个在一起的功能意义， 败血症隔离。最后，脓毒症期间细胞沿着肠道的迁移速度会减慢，细胞停留的时间几乎是原来的两倍。沿着肠道的迁移速度会减慢，细胞停留的时间几乎是原来的两倍 只要在脓毒症期间和在基础条件下一样，至少部分地由凋亡和增殖介导。 将确定减缓迁移的机制，包括改变渗透性的影响和 微生物组由于肠道在引发和传播危重疾病方面起着重要作用， 脓毒症中肠道完整性失调的机制对公共卫生具有重要意义， 这种疾病很常见，非常昂贵，而且致命性很高。

Sepsis is the leading cause of death among critically ill patients in the United States with between 230,000 and 370,000 people dying from the disease annually. Outside of antibiotics, treatment for sepsis is non-specific, and there are no approved therapeutics available once antibiotics and supportive therapy fail. The gut has long been characterized as the motor of multiple organ dysfunction syndrome. We have spent the three previous cycles of funding examining mechanisms of gut integrity (first apoptosis then proliferation, migration and permeability) in sepsis. This renewal is a logical next step in the evolution of how we view the gut in sepsis. We propose to assay the intestinal epithelium, immune system and microbiome, both in isolation and also in the context of how alterations in one compartment impact the others since we hypothesize this strategy will yield insights that can only be obtained using this more comprehensive approach. The first goal of the proposal is to understand mechanisms through which the immune system and microbiome alter survival in mice lacking the tight junction-associated protein junctional adhesion molecule-A (JAM-A), which have alterations in permeability, bacteremia and survival following sepsis. This will be done using a combination of mice with whole body and intestine-specific deletion of JAM-A as well as mice with controlled alterations in the endogenous bacteria. Further, intestinal permeability is controlled by two tight junction-dependent pathways and a tight junction-independent pathway. Each allows different size molecules to exit the gut lumen into the extraluminal environment. By genetically altering each of these pathways of permeability (the leak, pore and unrestricted pathways respectively), studies will determine the functional significance of each together and in isolation in sepsis. Finally, migration is slowed along the intestine during sepsis, with cells residing nearly twice as long during sepsis as under basal conditions, mediated, at least in part, by apoptosis and proliferation. Mechanisms of slowed migration will be determined including the impact of altering permeability and the microbiome. Since the gut plays a major role in both initiating and propagating critical illness, understanding mechanisms through which gut integrity is dysregulated in sepsis has significant public health implications in a disease that is common, very costly, and highly lethal.