Characterization of the Novel Protective Role of the Mast Cell in Colitis

描述（由申请人提供）：本提案描述了一个为期5年的培训计划，用于将候选人培养为独立科学家。伊丽莎白·列侬博士正在接受培训，成为北卡罗来纳州州立大学（NCSU）备受推崇的临床医生调查员项目的一员。她完成了兽医内科的结构化住院医师培训，并于2011年获得董事会认证。然后，她被一位名叫露丝·L·佩克特的人接受了一个竞争性的奖学金。Kirschstein机构培训补助金（T32）通过比较医学和转化研究中心，在那里她接受了优秀的基础科学培训博士亚当Moeser的实验室，研究肥大细胞在炎症性肠病（IBD）的作用。她现在建议通过一个具有互补专业知识领域的优秀导师团队，在无菌动物的使用，高通量测序技术和多重分析方面接受培训，在IBD研究的这个未充分研究的领域扩展她的科学技能。她提出的工作旨在开始解开肥大细胞在IBD中的复杂作用，这将使我们对这种疾病的病理生理学的理解朝着可能导致创新的IBD早期干预和新的治疗策略的方向发展。候选人的科学发展将在胃肠道生物学副教授Adam Moeser博士的主要指导下进行，他是一位创新的R 01资助的科学家，研究胃肠道中的肥大细胞生物学。为了加强培训，Lennon博士将由杜克大学病理学、免疫学和微生物学教授兼病理学研究生研究主任Soman Abraham博士和R.位于查佩尔山的北卡罗来纳州大学胃肠病学和肝病学教授Balfour Sartor说。这两位科学家都有R 01资助的良好记录，包括亚伯拉罕博士的MERIT奖。两人都曾指导过多名K获奖者和研究生，并致力于为列侬博士提供出色的科学和职业建议、指导和支持。列侬博士将有机会通过继续教育，研究研讨会，期刊俱乐部和NCSU和麻省理工学院的专业发展讲座获得许多专业发展和职业提升的机会。该提案旨在阐明肥大细胞在IBD发病机制中的新保护作用，该作用已被候选人的初步数据所证明。候选人最近的工作表明，肥大细胞在自发性结肠炎中具有保护作用; IL 10-/-小鼠中肥大细胞的缺乏导致结肠炎恶化。因此，了解这种保护作用的机制可能会为IBD患者或易患IBD的患者带来新的治疗甚至预防策略。中心假设是肥大细胞对于抑制IBD中的炎症至关重要，并且肥大细胞通过诱导T调节细胞（TcR）来抑制炎症，这需要肠道微生物群的存在。这项工作的具体目标是：1）该目标将在体内证明，MC调节结肠炎易感小鼠中结肠细胞因子产生和Treg数量，并且肠道微生物群影响MC介导的结肠中Treg的募集和分化。2)这一目标将解决的假设，即MC，与来自肠腔的微生物产物的相互作用，诱导幼稚的CD 4 + T细胞分化为TcB。这项工作将主要在NCSU完成，NCSU为完成所有拟议的研究提供了极好的资源。杜克大学将作为专门设备使用的次要地点，列侬博士将在查佩尔山的北卡罗来纳州大学接受额外的培训。NCSU的兽医学院为培训兽医临床医生-科学家提供了理想的环境，这些科学家精通使用和护理疾病的动物模型，并且可以成为比较医学的领导者，从而可以增强有益于人类医学的发现。这种环境最大限度地发挥了列侬博士建立科学利基的潜力，以形成她向独立研究事业的过渡。

DESCRIPTION (provided by applicant): This proposal describes a 5 year training program for the development of the candidate as an independent scientist. Dr. Elizabeth Lennon is being trained as a member of the highly regarded Clinician Investigator program at North Carolina State University (NCSU). She completed structured residency training in veterinary internal medicine and obtained board certification in 2011. She then was accepted into a competitive fellowship supported by a Ruth L. Kirschstein Institutional Training Grant (T32) through the Center for Comparative Medicine and Translational Research, where she received excellent basic science training in Dr. Adam Moeser's laboratory, studying the role of the mast cell in inflammatory bowel disease (IBD). She is now proposing to expand her scientific skills in this understudied area of IBD research through an excellent mentorship team with complementary areas of expertise, receiving training in the use of axenic animals, high- throughput sequencing techniques, and multiplex analysis. Her proposed work aims to begin to unravel the complex role of the mast cell in IBD and that will progress our understanding of the pathophysiology of this disease in a direction that may lead to innovative early interventions and novel treatment strategies for IBD. The candidate's scientific development will be under the primary mentorship of Dr. Adam Moeser, Associate Professor of Gastrointestinal Biology, who is an innovative, R01-funded scientist who studies mast cell biology in the gastrointestinal tract. To enhance the training, Dr. Lennon will be co-mentored by Dr. Soman Abraham, Professor of Pathology, Immunology, and Microbiology and Director of Graduate Studies in Pathology at Duke University, and Dr. R. Balfour Sartor, Professor of Gastroenterology and Hepatology at the University of North Carolina at Chapel Hill (UNC). Both of these scientists have an excellent track record of R01 funding, including a MERIT award for Dr. Abraham. Both have mentored multiple K awardees and graduate students and are committed to providing excellent scientific and career advice, direction, and support to Dr. Lennon. Dr. Lennon will have access to many opportunities for professional development and career enhancement through continuing education, research seminars, journal clubs, and professional development lectures at NCSU and UNC. The proposal will aim to elucidate the novel protective role of the mast cell in IBD pathogenesis that has been demonstrated by the candidate's preliminary data. The candidate's recent work has demonstrated that mast cells have a protective role in spontaneous colitis; absence of mast cells in IL10-/- mice results in worsened colitis. Therefore, understanding the mechanism of this protective effect could lead to novel therapeutic or even preventative strategies for IBD patients or those who are predisposed. The central hypothesis is that mast cells are critical for dampening inflammation in IBD, and that mast cells suppress inflammation by induction of T regulatory cells (Tregs), which requires the presence of the intestinal microbiota. The specific aims of this work are: 1) This aim will demonstrate, in vivo, that MCs regulate colonic cytokine production and Treg number in colitis-prone mice, and that the intestinal microbiota influences MC-mediated recruitment and differentiation of Tregs in the colon. 2) This aim will address the hypothesis that MCs, following interaction with microbial products from the intestinal lumen, induce differentiation of naive CD4+ T cells into Tregs. This work will primarily be completed at NCSU, which provides excellent resources for completing all the studies proposed. Duke University will serve as a secondary site for specialized equipment use, and Dr. Lennon will receive additional training at the University of North Carolina at Chapel Hill. The College of Veterinary Medicine at NCSU provides an ideal setting for training veterinary clinician-scientists who are proficient in the use of and care for animal models of disease, and who can become leaders in comparative medicine, which can enhance discoveries that benefit human medicine as well. This environment maximizes the potential for Dr. Lennon to establish a scientific niche to form her transition to an independent research career.