Thyroid Hormone and the Gut

描述(申请人提供)：在严重创伤和脓毒症的背景下，肠道屏障功能的崩溃被称为“多系统器官衰竭的运动”，但其潜在的病理生理机制尚不清楚。这一建议是基于一个新的假设，即肠道碱性磷酸酶(IAP)表达的丧失是危重患者肠粘膜防御功能受损的基础。尽管IAP是隐窝-绒毛分化的著名标记物，但其生理作用尚不清楚。我们现在认为，IAP代表了一种以前未被认识到的肠道防御机制，旨在保护有机体免受细菌和毒素的伤害。这项建议的主要目标是(1)确定IAP保护有机体免受管腔环境影响的机制，(2)证明这种新发现的肠道粘膜防御系统组件在体内确实存在，以及(3)为基于IAP的治疗奠定基础。在目标1中，体外模型系统将被用来检验IAP保护有机体免受细菌(如沙门氏菌)和毒素(LPS)的伤害的机制。WT和IAP表达细胞将被用来识别IAP的细胞靶点，描述其保护宿主细胞的作用机制。在目标2中，将在WT和IAP KO小鼠身上使用体内模型系统，以评估其在肠道粘膜防御方面的功能作用。小肠缺血和肠腔沙门氏菌/脂多糖将被用来测试肠道屏障保护宿主免受感染、败血症和最终器官损害的能力。目的#3旨在确定在各种疾病状态下利用IAP作为靶点的有效性。这两种脓毒症/损伤模型将应用于IAP表达缺失的两种易感性条件下，即饥饿和甲状腺功能减退。这些对IAP、KO和转基因小鼠的研究将使我们能够确定IAP在伴随临床相关疾病状态的肠道屏障功能障碍中所起的作用。综上所述，这些研究将阐明IAP的功能及其作用机制，并旨在为IAP靶向治疗提供“原则证据”，这些治疗可用于临床环境中，以维持肠粘膜防御功能。在外行方面，我们将探索一种以前不为人知的机制，这种生物已经开发出保护自己免受胃肠道内有害物质伤害的机制，为帮助危重患者的治疗奠定了基础。 拟议的研究将探索一种以前未知的肠粘膜防御机制，涉及肠道刷状边界酶，肠碱性磷酸酶(IAP)。这些研究将阐明IAP的功能及其作用机制，并旨在为IAP靶向治疗提供“原则证据”，这些治疗可用于临床环境中以维持肠粘膜防御功能。

DESCRIPTION (provided by applicant): In the setting of severe trauma and sepsis, a breakdown in gut barrier function has been termed the "motor of multi-system organ failure", but the underlying pathophysiology is unknown. This proposal is based upon a novel hypothesis that the loss of intestinal alkaline phosphatase (IAP) expression underlies the impairment in gut mucosal defense that occurs in critically ill patients. Although IAP is a well-known marker for crypt-villus differentiation, its physiological role has not been elucidated. We now believe that IAP represents a previously unrecognized gut defense mechanism that is designed to protect the organism from bacteria and toxins. The broad goals of this proposal are to (1) define the mechanisms by which IAP protects the organism from the luminal environment, (2) prove that this newly recognized component of the gut mucosal defense system actually exists in vivo, and (3) lay the groundwork for IAP-based therapies. In Aim #1, in vitro model systems will be used to examine the mechanisms by which IAP protects the organism from luminal bacteria (e.g., Salmonella) and toxins (LPS). WT and IAP-expressing cells will be employed to identify the cellular targets for IAP, delineating its mechanism of action in protecting the host cell. In Aim #2, in vivo model systems will be employed in WT and IAP KO mice in order to assess its functional role in regard to gut mucosal defense. Small intestinal ischemia and luminal Salmonella/LPS will be used to test the ability of the intestinal barrier to protect the host from infection, sepsis, and end organ damage. Aim #3 is designed to establish the efficacy of utilizing IAP as a target in the context of a variety of disease states. The two models of sepsis/injury will be applied in the contexts of two susceptibility conditions in which IAP expression is lost, starvation and hypothyroidism. These studies in IAP KO and transgenic mice will allow us to determine the role that IAP plays in the gut barrier dysfunction that accompanies clinically relevant disease states. Taken together, these studies will elucidate the functions of IAP and its mechanisms of action, and are designed to provide the "proof of principle" for IAP-targeted therapies that could be used in the clinical setting to maintain gut mucosal defense function. In lay terms, we will explore a previously unrecognized mechanism that the organism has developed to protect itself from harmful substances within the gastrointestinal tract, laying the groundwork for treatments that will aid critically-ill patients. The proposed studies will explore a previously unrecognized gut mucosal defense mechanism involving the intestinal brush border enzyme, intestinal alkaline phosphatase (IAP). The studies will elucidate the functions of IAP and its mechanisms of action, and are designed to provide the "proof of principle" for IAP- targeted therapies that could be used in the clinical setting to maintain gut mucosal defense function.