Mechanisms and Prevention of TGF-beta-induced Intestinal Fibrosis

这项建议描述了一个3-vear培训方案，用于在#年发展学术研究事业。 炎症性肠病的翻译研究。首席研究员已经完成了分子 生物学培训(博士)和临床研究培训(理学硕士)，现在将把基础科学和临床联系起来 在孤儿核受体生物学和转基因啮齿动物模型方面的补充培训研究技能 肠纤维化症。这将提供一个关键的链接，使候选人能够翻译基础科学发现 用于未来的人类临床研究。培训计划将发展候选人在核能方面的技能 受体生物学、肌成纤维细胞生物学和肠道纤维化 优秀的指导团队。 肠纤维化专家Ellen Zimmermann博士将与Sem博士一起加入指导团队 Phan，肌成纤维细胞生物学专家，Victor Thanickal博士，肺部疾病的翻译研究员 贝特伦·皮特博士，研究螺内酯在心脏纤维化和心脏中的作用的临床研究人员 失败了。密歇根大学的胃肠病学部提供了理想的培训环境 通过将来自多个资源的专业知识整合到定制培训中，实现转化型医生-科学家 为学术生涯发展而设的课程。这种环境非常有利于启动 希金斯博士的翻译研究生涯。 拟议中的研究将集中在肠纤维化上，这是克罗恩病的一种令人恐惧的并发症，没有 有效的医疗治疗。长期的研究目标是阐明转化生长因子|31驱动的机制 肠纤维化，并利用这一信息来针对可以预防或逆转的抗纤维化治疗 肠道纤维化。我们的初步数据支持我们的中心假设，即螺内酯具有一种新颖的 属性，通过激活孤儿来抑制通过Smad2和Smad3传递的信号的能力 核受体，PXR(孕烷X受体)。 具体目的包括：(1)确定螺内酯是否利用孕烷X的激活 受体(PXR)，以防止Smad2和Smad2的磷酸化、核转位或转录活性 Smads在转化生长因子-(31)刺激成纤维的结肠肌成纤维细胞；和(2)确定螺内酯是否 能抑制大鼠和小鼠慢性炎症性肠病模型的肠纤维化。 这些研究将有助于深入了解TGF31驱动的肠纤维化的机制，将有助于 应聘者培养成为独立调查员的基本技能，并可能为 抗纤维化治疗的未来转化性应用。这项研究与公共卫生高度相关 因为克罗恩病影响了60多万美国人；我们没有预防肠道纤维化的疗法； 目前，这些患者中有75%最终将需要手术治疗纤维性肠道狭窄。

This proposal describes a 3-vear training program for the development of an academic research career in translational research in inflammatory bowel disease. The principal investigator has completed molecular biology training (Ph.D.), and clinical research training (M.Sc.), and will now link basic science and clinical research skills with supplementary training in orphan nuclear receptor biology and transgenic rodent models of intestinal fibrosis. This will provide a critical link to enable the candidate to translate basic science findings to future clinical research in humans. The training program will develop the candidate's skills in nuclear receptor biology, myofibroblast biology, and intestinal fibrosis, through structured learning and an outstanding mentoring team. Dr. Ellen Zimmermann, an expert in intestinal fibrosis, will be joined on the mentoring team by Dr. Sem Phan, an expert in myofibroblast biology, Dr. Victor Thannickal, a translational researcher in pulmonary fibrosis, and Dr. Bertram Pitt, a clinical researcher of the role of spironolactone in cardiac fibrosis and heart failure. The Gastroenterology Division at the University of Michigan provides an ideal setting for training translational physician-scientists by incorporating expertise from many resources into customized training programs for academic career development. This environment is highly advantageous for launching the translational research career of Dr. Higgins. The proposed research will focus on intestinal fibrosis, a feared complication of Crohn's disease with no effective medical treatments. The long-term research goal is to elucidate the mechanisms of TGF|31-driven intestinal fibrosis and to use this information to target anti-fibrotic therapies that can prevent or reverse intestinal fibrosis. Our preliminary data drives our central hypothesis, that spironolactone has a novel property, the ability to inhibit TGF(31 signaling via SMAD2 and SMAD3 through its activation of the orphan nuclear receptor, PXR (pregnane X receptor). The specific aims include: (1) To determine whether spironolactone utilizes activation of the pregnane X receptor (PXR)to prevent phosphorylation, nuclear translocation, or the transcriptional activity of Smad2 and SmadS in TGF-(31 stimulated fibrogenic colonic myofibroblasts; and (2) To determine whether spironolactone can inhibit intestinal fibrosis in rat and mouse models of chronic inflammatory bowel disease. These studies will provide insight into the mechanisms of TGF31 -driven intestinal fibrosis, will help the candidate develop essential skills to become an independent investigator, and may provide the basis of future translational applications of anti-fibrotic therapy. This research is highly relevant to public health because Crohn's disease affects over 600,000 Americans; we have no therapy to prevent intestinal fibrosis; and currently -75% of these patients will eventually require surgery for fibrotic intestinal strictures.