Mechanisms and Prevention of TGF-beta-induced Intestinal Fibrosis

描述(由申请人提供)： 本提案描述了一项为期3年的培训计划，旨在发展炎症性肠病翻译研究的学术研究生涯。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研究技能与孤儿核受体生物学和肠道纤维化转基因啮齿动物模型的补充培训联系起来。这将提供一个关键的链接，使候选人能够将基础科学发现转化为未来的人类临床研究。培训计划将通过有组织的学习和出色的指导团队，发展候选人在核受体生物学、肌成纤维细胞生物学和肠道纤维化方面的技能。肠道纤维化专家艾伦·齐默尔曼博士将与肌成纤维细胞生物学专家塞姆·潘博士、肺纤维化翻译研究员维克托·坦尼卡尔博士和研究螺内酯在心脏纤维化和心力衰竭中的作用的临床研究员伯特伦·皮特博士一起加入指导团队。密歇根大学的胃肠病学部通过将多种资源的专业知识整合到针对学术生涯发展的定制培训计划中，为培训转化型内科医生-科学家提供了理想的环境。这种环境对希金斯博士开展翻译研究事业非常有利。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恐惧的并发症，没有有效的药物治疗。长期的研究目标是阐明转化生长因子1驱动的肠纤维化的机制，并利用这些信息针对可以预防或逆转肠纤维化的抗纤维化治疗。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的特性，即通过激活孤儿核受体PXR(孕烷X受体)，通过Smad2和Smad3抑制转化生长因子1信号的能力。 具体目的包括：(1)确定螺内酯是否通过激活孕烷X受体(PXR)来防止转化生长因子-1[SIC]刺激的纤维化结肠肌成纤维细胞中Smad2和Smads的磷酸化、核移位或Smad2和Smads的转录活性；(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的肠纤维化。 这些研究将提供对转化生长因子1驱动的肠纤维化的机制的洞察，将帮助候选人培养成为独立研究人员的基本技能，并可能为未来抗纤维化治疗的翻译应用提供基础。这项研究与公共卫生高度相关，因为克罗恩病影响着60多万美国人；我们没有预防肠道纤维化的治疗方法；目前，这些患者中约75%最终将需要手术治疗纤维性肠道狭窄。

DESCRIPTION (provided by applicant): This proposal describes a 3-year 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¿1-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¿1 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-¿1 [sic] 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 TGF¿1 -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.