Thyroid Hormone and the Gut

描述（由申请人提供）：在严重创伤和败血症的情况下，肠道屏障功能的破坏被称为“多系统器官衰竭的运动”，但其潜在的病理生理学尚不清楚。这一建议是基于一种新的假设，即肠道碱性磷酸酶（IAP）表达的丧失是危重患者肠道黏膜防御功能受损的基础。虽然IAP是众所周知的隐绒毛分化标志物，但其生理作用尚未阐明。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，旨在保护生物体免受细菌和毒素的侵害。本提案的总体目标是：(1)确定IAP保护生物体免受腔内环境影响的机制，(2)证明这种新发现的肠道黏膜防御系统成分在体内确实存在，(3)为基于IAP的治疗奠定基础。在目标1中，体外模型系统将用于检查IAP保护生物体免受肠道细菌（如沙门氏菌）和毒素（LPS）侵害的机制。我们将利用WT和表达IAP的细胞来鉴定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小鼠中使用体内模型系统，以评估其在肠道黏膜防御方面的功能作用。小肠缺血和肠道沙门氏菌/LPS将用于测试肠道屏障保护宿主免受感染、败血症和终末器官损伤的能力。Aim #3旨在确定在各种疾病状态下利用IAP作为靶标的有效性。这两种脓毒症/损伤模型将应用于IAP表达丢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“原理证明”，可用于临床维持肠道黏膜防御功能。通俗地说，我们将探索一种以前未被认识到的机制，即生物体已经发展到保护自己免受胃肠道内有害物质的侵害，为帮助危重病人的治疗奠定基础。

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.