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

胆汁酸通常与胃肠道中膳食脂质的消化有关。然而，在过去的几年里，胆汁酸已经涉及到其他生物过程。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。储存在胆囊后，它们被排出小肠作为进食的反应。约95%的肠道胆汁酸最终被远端小肠上皮重吸收，并通过循环运输回肝脏。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，控制着身体的整体代谢和生理状态。本研究的目的是研究胆汁酸对Paneth细胞功能的影响，Paneth细胞是小肠的一种分泌细胞，参与调节肠道的生理和免疫景观。在本提案中，我们计划确定Paneth细胞感知和响应胆汁酸的能力，并确定参与这种感知和响应的分子机制，并评估胆汁酸信号传导在Paneth细胞功能的选定方面的作用，如抗菌蛋白和肽的合成和分泌。我已经开发了初步数据，表明Paneth细胞产生的抗菌肽对肠道胆汁酸池有反应。我们计划利用先进的遗传、生化、分子和免疫组织化学技术结合实验动物模型来证明这一假设。本提案针对肝胆和肠道功能之间的关系，并将探讨两个明显分离的胃肠生理学方面的可能联系。本研究将有助于了解胆汁酸作为激素在维持肠道微环境中的作用，以及Paneth细胞功能的分子机制。

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.