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

描述(由申请者提供)：本建议书描述了一项为期5年的培训计划，以培养候选人成为一名独立科学家。伊丽莎白·列侬博士正在接受培训，成为北卡罗来纳州立大学(NCSU)备受尊敬的临床医生研究员项目的成员。她完成了兽医内科的结构化住院医师培训，并于2011年获得了董事会认证。随后，她通过比较医学和转化研究中心获得了Ruth L.Kirschstein院校培训补助金(T32)资助的竞争性奖学金，在那里她在Adam Moeser博士的实验室接受了出色的基础科学培训，研究肥大细胞在炎症性肠病(IBD)中的作用。她现在提议通过一个优秀的导师团队来扩展她在这一未被研究的IBD研究领域的科学技能，该团队具有互补的专业知识领域，接受关于使用无菌动物、高通量测序技术和多重分析的培训。她提出的工作旨在开始解开肥大细胞在IBD中的复杂作用，这将促进我们对这种疾病的病理生理学的理解，可能导致创新的早期干预措施和新的IBD治疗策略。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，Adam Moeser博士是一位由R01资助的创新科学家，研究胃肠道肥大细胞生物学。为了加强培训，列侬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博士和北卡罗来纳大学教堂山分校(UNC)胃肠病和肝病教授R.Balfour Sartor博士共同指导。这两位科学家在R01资助方面都有出色的记录，包括为亚伯拉罕博士颁发的优秀奖。两人都曾指导过多名K奖获得者和研究生，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。列侬博士将通过继续教育、研究研讨会、期刊俱乐部以及在NCSU和北卡罗来纳大学的职业发展讲座，获得许多职业发展和职业提升的机会。该提案旨在阐明肥大细胞在IBD发病机制中的新的保护作用，这一作用已被候选人的初步数据所证明。这位候选人最近的研究表明，肥大细胞在自发性结肠炎中具有保护作用；在IL10-/-小鼠中缺乏肥大细胞会导致结肠炎恶化。因此，了解这种保护作用的机制可能会为IBD患者或易患IBD的人带来新的治疗甚至预防策略。中心假设是肥大细胞对抑制IBD的炎症至关重要，肥大细胞通过诱导T调节细胞(Tregs)抑制炎症，这需要肠道微生物区系的存在。这项工作的具体目标是：1)这一目标将在体内证明MC调节结肠炎易感小鼠结肠细胞因子的产生和Treg数量，以及肠道微生物区系影响MC介导的Treg在结肠中的募集和分化。2)这一目标将解决以下假设，即MC在与肠道微生物产物相互作用后，诱导初始的CD4+T细胞分化为Tregs。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。杜克大学将作为专业设备使用的第二地点，列侬博士将在北卡罗来纳大学教堂山分校接受额外培训。NCSU的兽医学院为培养兽医临床医生提供了理想的环境，这些医生是精通使用和护理疾病动物模型的科学家，可以成为比较医学的领导者，这可以促进有益于人类医学的发现。这种环境最大限度地增加了列侬博士建立科学利基的潜力，从而形成了她向独立研究生涯的过渡。

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.