The role of bile acids in the control of Paneth cells function

胆汁酸通常与胃肠道对膳食脂肪的消化有关。然而，在过去的几年里，胆汁酸被牵连到其他生物过程中。胆汁酸同时存在于多个身体隔室中；它们由肝脏产生(或重新吸收)，并入胆汁，然后从肝脏排入胆囊。在胆囊中储存后，它们被排入小肠作为对喂养的反应。大约95%的肠道胆汁酸最终被远端小肠上皮重新吸收，并通过循环输送回肝脏。这是一个高度受控的循环，被认为是传递多种信号的主要方式，这些信号控制着身体的整体代谢和生理状态。这项建议的目的是研究胆汁酸对潘氏细胞功能的影响，潘氏细胞是小肠的一种分泌细胞类型，参与调节肠道的生理和免疫格局。在这项建议中，我们计划确定潘氏细胞感知和响应胆汁酸的能力，并确定参与这种感知和反应的分子机制，并评估胆汁酸信号在潘氏细胞功能的某些方面的影响，如抗菌蛋白和多肽的合成和分泌。我已经开发了初步数据，表明潘氏细胞产生的抗菌肽对肠道胆汁酸池有反应。我们计划使用先进的遗传学、生化、分子和免疫组织化学技术的组合，通过实验动物模型来证明这一假说。这项建议的目标是肝胆功能和肠道功能之间的关系，并将探索胃肠生理两个明显分离的方面之间的假定联系。本研究将有助于理解胆汁酸作为激素的作用以及潘氏细胞在维持肠道微环境中作用的分子机制。

Bile acids are typically associated with the digestion of dietary lipids in the gastrointestinal tract. However, over the past few years, bile acids have been implicated in other biological processes. Bile acids are simultaneously present in multiple body compartments; they are produced (or reabsorbed) by the liver, incorporated into the bile and drained from the liver into the gallbladder. After storage in the gallbladder, they are discharged into the small intestine in response to feeding. About 95% of the intestinal bile acids are eventually reabsorbed by the distal small bowel epithelium and transported back to the liver through the circulation. This is a highly-controlled cycle, which is thought to be a major way to convey multiple signals that control the overall metabolical and physiological status of the body. The objective of this proposal is to study the effects of bile acids over the function of Paneth cells, a secretory cell type of the small intestine that is involved in modulating the physiological and immunological landscape of the gut. In this proposal, we plan to determine to the capacity of Paneth cells to sense and respond to bile acids, as well as to identify the molecular mechanisms involved in such sensing and response, and evaluate the effects of bile acids signaling in selected aspects of Paneth cells function, such as the synthesis and secretion of antimicrobial proteins and peptides. I have developed preliminary data suggesting that the production of antimicrobial peptides by Paneth cells is responsive to the intestinal bile acids pool. We plan to demonstrate this hypothesis using a combination of advanced genetic, biochemical, molecular and immunohistochemical techniques using experimental animal models. This proposal targets the relationship between hepatobiliary and intestinal functions, and will explore the putative connection between two apparently separated aspects of gastrointestinal physiology. This study will contribute to the understanding of the role of bile acids as hormones as well as the molecular mechanisms of Paneth cell function in the maintenance of the intestinal microenviroment.