Role of Bile Acids in the Initiation of Liver Regeneration

描述(由申请人提供)： 这项研究的重点是肝脏再生和这一现象的最初触发因素。胆汁酸是由胆固醇制成的洗涤剂分子，有助于溶解脂肪在肠道中吸收。胆汁酸是由肝细胞制造的，排泄到肠道中，每天几乎不会损失。这一建议的假设是，当未受损伤的非胆汁淤积性肝脏遇到超过肝脏最大分泌量的胆汁酸时，再生就会启动。目的1利用肝部分切除模型确定胆汁酸在启动肝再生中的作用。在目标2中，通过门静脉给药的胆汁酸模型将允许在没有其他损伤的情况下重点研究胆汁酸对肝脏的影响。最后，目标3将研究胆汁酸内流转运体和核受体信号在胆汁酸依赖型肝再生中的作用。总而言之，这些研究将仔细研究胆汁酸对畅通肝脏的影响，并确定胆汁酸如何参与触发肝脏再生。 本提案描述了肝脏病学领域翻译研究学术生涯发展的五年计划。这位首席研究员已经完成了内科住院医师、胃肠病学研究员和实验室博士后研究员的工作，该实验室专注于肝脏炎症背景下的基因调控和信号转导。该提案将促进主要研究人员对分子生物学和生理学的掌握，因为这与肝脏再生和肝癌发生有关，并为他作为一名独立研究人员的职业生涯做好准备。马库斯·格罗姆佩博士将指导该提案的科学方面，主要调查员已经组建了一个顾问团队，他们将帮助实现提案中概述的科学和职业目标。格罗姆佩博士是肝细胞增殖领域公认的领导者，他有能力指导这一项目。该实验室资金充足，拥有适当的设备和支持人员，并且存在于支持俄勒冈健康与科学大学这类研究的环境中。 公共卫生相关性： 这一贡献意义重大，因为它有望为肝脏再生提供一个生理原因，可用于控制肝细胞增殖，以预防和治疗最常见的肝脏疾病状态。

DESCRIPTION (provided by applicant): This research focuses on liver regeneration and the initial triggers of this phenomenon. Bile acids are detergent molecules made from cholesterol which help solubilize fats for absorption in the intestine. Bile acids are made by hepatocytes, excreted into the intestine, and recirculated with little loss each day. The hypothesis of this proposal is that when the uninjured non-cholestatic liver encounters bile acids exceeding the maximum secretory capacity of the liver, regeneration is initiated. Aim 1 will determine the role of bile acids in the initiation of liver regeneration using a model of partial hepatectomy. In Aim 2 a model of bile acid administration through the portal vein will allow the focused study of the effects of supraphysiolgic levels bile acids on the liver in the absence of other injury. Lastly, Aim 3 will examine the contribution of the bile acid influx transporter and nuclear receptor signaling in bile acid-dependent liver regeneration. In summary, these studies will closely examine the effects of bile acids on the unobstructed liver, and determine how bile acids are involved in the triggering of liver regeneration. This proposal describes a five year plan for the development of an academic career in translational research in the field of Hepatology. The prinicipal [sic] investigator has completed a residency in Internal Medicine, a fellowship in Gastroenterology, and a post-doctoral fellowship in a laboratory focused on gene regulation and signal transduction in the context of hepatic inflammation. The proposal will promote the primary investigator's command of molecular biology and physiology as it relates liver regeneration and hepatocarcinogenesis, and prepare him for a career as an independent investigator. Dr. Markus Grompe will mentor the scientific aspects of the proposal, and the primary investigator has assembled a team of advisors who will assist in achieving the scientific and career goals outlined in the proposal. Dr. Grompe is a recognized leader in the field hepatocyte proliferation and is well-equipped to mentor this project. The laboratory is well-funded, has the appropriate equipment and support personnel, and exists in an environment supportive of this type of research at Oregon Health & Sciences University. PUBLIC HEALTH RELEVANCE: This contribution is significant because it is expected to provide a physiological reason for liver regeneration which can be used to manipulate hepatocyte proliferation for the purposes of preventing and treating the most common liver disease states.