Mechanisms and Prevention of TGF-beta-induced Intestinal Fibrosis

本提案描述了一个3-vear培训计划的学术研究生涯的发展， 炎症性肠病的转化研究。主要研究者已经完成了分子 生物学培训（博士），和临床研究培训（硕士），现在将把基础科学和临床 孤儿核受体生物学和转基因啮齿动物模型的研究技能， 肠纤维化这将提供一个关键环节，使候选人能够翻译基础科学发现 未来的人类临床研究。该培训计划将培养候选人的核技能 受体生物学、肌成纤维细胞生物学和肠纤维化，通过结构化学习和 优秀的指导团队。 艾伦·齐默尔曼博士是肠道纤维化方面的专家，他将与萨姆博士一起加入指导小组。 Phan博士，肌成纤维细胞生物学专家，维克托Thannickal博士，肺纤维化转化研究员， Bertram Pitt博士，一位研究螺内酯在心脏纤维化和心脏病中作用的临床研究者。 失败密歇根大学胃肠病学分部为培训提供了理想的环境 通过将来自许多资源的专业知识纳入定制培训， 学术职业发展计划。这种环境非常有利于启动 希金斯博士的转化研究生涯 这项拟议中的研究将集中在肠道纤维化上，这是克罗恩病的一种令人担忧的并发症， 有效的医学治疗。长期的研究目标是阐明TGF的作用机制|31驱动 肠纤维化，并利用这些信息来靶向抗纤维化治疗， 肠纤维化我们的初步数据支持我们的中心假设，即螺内酯具有新颖的 通过SMAD 2和SMAD 3激活孤儿细胞，抑制TGF β 1信号传导的能力 核受体，PXR（胆甾烷X受体）。 具体目的包括：（1）确定螺内酯是否利用了β-羟色胺X的活化作用 受体（PXR），以防止磷酸化，核转位，或Smad 2的转录活性， SmadS在TGF-β 1刺激的纤维化结肠肌成纤维细胞中的表达;（2）确定螺内酯是否 可以抑制慢性炎症性肠病大鼠和小鼠模型中的肠纤维化。 这些研究将为深入了解TGF 31驱动的肠纤维化机制提供帮助， 候选人发展成为独立调查员的基本技能，并可能提供以下基础： 抗纤维化治疗的未来转化应用。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治疗方法; 并且目前这些患者中的约75%将最终需要手术治疗纤维化肠狭窄。

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.