Mechanisms of Intestinal Integrity in Sepsis and Shock

脓毒症是美国危重病人的主要死亡原因，在23万至23万人之间 每年有37万人死于这种疾病。除抗生素外，脓毒症的治疗是非特异性的， 而且，一旦抗生素和支持疗法失败，就没有批准的治疗方法可用。胆量已经很长了 被描述为多器官功能障碍综合征的运动。我们在过去的三年里 检查肠道完整性机制的资金周期(首先是凋亡，然后是增殖、迁移和 渗透性)在败血症中。这种更新是我们在脓毒症中看待肠道的进化的合乎逻辑的下一步。我们 建议对肠道上皮细胞、免疫系统和微生物组进行分离和检测。 一个隔间的变化如何影响其他隔间的背景，因为我们假设这个策略将产生 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群改变缺乏免疫的小鼠存活的机制 紧密连接相关蛋白连接黏附分子-A(JAM-A)，它在 败血症后的通透性、菌血症和存活率。这将通过结合使用鼠标和 全身和肠道特异缺失JAM-A以及控制改变的小鼠 内源性细菌。此外，肠道通透性由两条紧密连接依赖的通路控制。 和紧密连接非依赖的途径。每一种都允许不同大小的分子离开肠腔进入 外在环境。通过基因改变这些渗透性的每一条途径(渗漏、孔洞和 不受限制的通路)，研究将确定每个通路一起和在一起的功能意义 败血症时的隔离。最后，在脓毒症期间，细胞沿肠道的迁移速度减慢，细胞驻留了近两次。 只要在脓毒症期间和在基础条件下一样，至少部分地由细胞凋亡和增殖介导。 将确定缓慢迁移的机制，包括改变渗透率的影响和 微生物组。由于肠道在引发和传播危重疾病方面发挥着重要作用，因此理解 脓毒症患者肠道完整性失调的机制具有重大的公共卫生意义 这种疾病很常见，代价很高，而且极具致命性。

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.