Very Early-onset inflammatory bowel disease

描述（由申请人提供）：我目前是费城儿童医院（CHOP）胃肠病学，肝病学和营养学部门的助理教授，于2009年6月在CHOP完成了胃肠病学奖学金。为了获得转化研究的培训，我在宾夕法尼亚大学（UPENN）医学院的转化和治疗医学研究所（ITMAT）完成了转化研究硕士学位（MTR）。我现在正在申请一个以患者为导向的研究职业发展（K23）奖，以发展IBD的高级研究技能，成为专注于极早发型炎症性肠病（VEO-IBD）转化研究的独立研究者。这次培训将使我有机会获得宝贵的经验，进行以患者为导向的研究，将基础科学进展与临床表型联系起来，以产生评估和治疗这些儿童的方法。我的短期目标是获得额外的培训和经验，设计，进行和分析以患者为导向的转化研究，研究我们独特的VEO-IBD患者人群。我的长期目标是在这个队列中领导前瞻性转化研究，合作和整合基因组学，微生物学和免疫学，为这些患者提供个性化治疗。从奖学金毕业后，在我导师的指导下，我领导了一项关于儿科CD口腔微生物组的研究。这使我能够发展实验室研究技能，并开始培养研究设计和数据分析的技能。为了配合这一主题， 我和我的导师加里吴博士一起写了一篇关于"肠道微生物群，现代社会的环境和疾病，以及" IBD和微生物组的评论。“在此期间，我对IBD的幼儿产生了兴趣，这既因为疾病的严重表现，也因为他们的护理方法缺乏共识。除了研究这些儿童的微生物组之外，我还对了解他们疾病的强大遗传贡献感兴趣。我对他们对英夫利西单抗治疗的不良反应的评价开始解决这个问题，数据已提交出版。我最近的试点项目利用全外显子组测序来检测疾病的新的和罕见的致病变异，进一步探讨了这个问题，并为这个项目产生了初步数据。这些经历帮助我形成了K23和我的职业目标。我现在需要进一步的培训来实现这些目标，因为我未来的研究以及对这个队列的最佳护理，集中在VEO-IBD患者的基因组，微生物组，免疫学和表型分析的整合上。因此，我沿着我的导师们，设计了这个K-23中提出的指导性科学和教育计划，包括（1）与我的研究兴趣密切相关的领域的正式教学指导，如基因组学和免疫学（2）与计算基因组学的高级教师一起指导研究导师，流行病学和免疫学（3）与相关领域的专家学院开展结构性合作（4）负责任地开展研究和遗传研究伦理方面的培训（5）完成本申请中描述的研究计划（6）在宾夕法尼亚大学和CHOP的其他发展活动。在资深教师的密切指导和指导下，我将进行越来越独立的临床研究。在这个K23奖的后期，我将提交申请，申请研究人员发起的研究，如R01。我的职业发展的一个组成部分将是由高级临床研究人员提供的指导。Marcella德沃托博士，博士，是这个研究职业发展奖的主要赞助商。该提议说明如下。发生在6岁以下儿童中的炎症性肠病被称为VEO-IBD。患有VEO-IBD的儿童通常比成人有更严重的症状和更大程度的胃肠道受累。疾病的严重程度和年轻的表现年龄表明更明显的遗传和失调的免疫反应比老年患者。例如，在几例重度VEO-IBD患者中发现了IL10R基因变异，目前适用干细胞移植而非抗TNF α治疗。然而，大多数VEO-IBD病例的原因尚不清楚。因此，鉴定这些和其他免疫缺陷对于开发用于治疗VEO-IBD人群的临床算法至关重要。在CHOP就诊的VEO-IBD患者人群提供了一个机会，可以解决有关VEO-IBD临床病程的实质性问题，并确定具有特定遗传异常的患者亚组。该提案的目的是检验以下总体假设：VEO-IBD代表一种独特的IBD形式，具有严重侵袭性疾病的高风险，并且是由一组独特的遗传变异引起的，而不是迟发型IBD。如果成功，这一建议将对EO-IBD儿童的诊断和治疗产生重大影响，也可能揭示IBD的一般原因。我们的具体目标是：1）确定VEO-IBD是否与晚发型儿科IBD相比，与更严重的短期病程（定义为需要早期手术或难治性生长衰竭）相关; 2）确定已知IBD基因座在VEO-IBD中的作用，并鉴定新的致病突变; 3）鉴定儿科IBD早期手术的遗传和表型预测因子。通过融合新技术，基因组学，IBD，流行病学和免疫学，最终微生物组，拟议的研究将成为一个杰出的平台，我将能够建立一个独立的研究路线。

DESCRIPTION (provided by applicant): I am currently an Assistant Professor in the Division of Gastroenterology, Hepatology, and Nutrition at The Children's Hospital of Philadelphia (CHOP), having completed a Gastroenterology fellowship at CHOP in June 2009. In order to obtain training in translational research, I completed a Masters of Translational Research (MTR) at the Institute of Translational and Therapeutic Medicine (ITMAT), at the University of Pennsylvania (UPENN) School of Medicine. I am now applying for a Mentored Patient-Oriented Research Career Development (K23) Award to develop advanced research skills in IBD to become an independent investigator in translational research focusing on very early-onset inflammatory bowel disease (VEO-IBD). This training will afford me the opportunity to gain valuable experience in conducting patient-oriented research linking basic science advances with clinical phenotype to generate an approach in the evaluation and treatment of these children. My short-term goals are to obtain additional training and experience in the design, conduct and analyses of patient-oriented translational research studying our unique VEO-IBD patient population. My long- term goal is to lead prospective translational studies in this cohort, collaborating and integrating genomics, microbiology and immunology to individualize therapy for these patients. Following graduation from fellowship, under the guidance of my mentors, I led a study on the oral microbiome in pediatric CD. This allowed me to develop bench research skills and begin to cultivate skills in study design and data analysis. In concert with this theme, with my mentor Gary Wu, MD I wrote a review on the "Gut Microbiota, environment and diseases of modern society, and on "IBD and the Microbiome." During this time, I became interested in the very young children with IBD, both by the severe presentation of disease as well as by the lack of consensus of approach in their care. In addition to my goal of studying the microbiome of these children, I became interested in understanding the strong genetic contribution to their disease. My evaluation on their poor response to infliximab therapy begins to address this question and the data has been submitted for publication. My recent pilot project utilizing whole exome sequencing to detect novel and rare causal variants of disease further explores this question and generated the preliminary data for this project. These experiences have helped shaped this proposed K23 and my career goals. I am now in need of further training to achieve these goals as my future research as well as optimal care of this cohort, centers on the integration of genomic, microbiome, immunologic and phenotypic analysis of patients with VEO-IBD. Therefore, I along with my mentors, have designed the mentored scientific and educational program proposed in this K-23, consisting of (1) formal didactic instruction in areas germane to my research interests, such as genomics and immunology (2) mentored research preceptorship with senior faculty in computational genomics, epidemiology and immunology (3) structured collaboration with expert faculty in related fields (4) training in the responsible conduct of research and ethics of genetic research (5) completion of the Research Plan described in this application (6) additional developmental activities at UPENN and CHOP. Under the close mentorship and guidance of senior faculty, I will perform increasingly independent clinical research. In the later years of this K23 Award, I will submit applications for investigator-initiated research, such as R01s. An integral part of my career development will be the mentorship provided by senior clinical investigators. Dr. Marcella Devoto, PhD., is the primary Sponsor of this Research Career Development Award. The proposal is described below. Inflammatory bowel disease occurring in children less than 6 years of age is known as VEO-IBD. Children with VEO-IBD often have more severe symptoms and a greater extent of GI tract involvement than adults. The severity of illness and young age of presentation suggest a more pronounced genetic and dysregulated immune response than in older patients. For example, variants in the IL10R gene have been identified in several patients with severe VEO-IBD, for whom stem cell transplantation, rather than anti-TNF α therapy, is now indicated. However, the causes of most VEO-IBD cases are unknown. Thus, identification of these and other immunodeficiencies is critically important to the development of clinical algorithms used to treat the VEO-IBD population. The population of VEO-IBD patients seen at CHOP presents an opportunity to address substantive questions regarding the clinical course of VEO-IBD and to identify subgroups of patients with specific genetic abnormalities. The goal of this proposal is to test the overall hypothesis that VEO-IBD represents a distinct form of IBD with a high risk of severe, aggressive disease and is caused by a distinct set of genetic variants than later-onset IBD. If successful, this proposal will have a major impact on the diagnosis and treatment of children with EO-IBD and may also shed light on the causes of IBD in general. Our specific goals are: 1) To determine whether VEO-IBD is associated with a more severe short term disease course defined as the need for early surgery or refractory growth failure, than later onset pediatric IBD; 2) To define the role of known IBD loci in VEO-IBD and identify new causal mutations; 3) To identify those genetic and phenotypic predictors of early surgery in pediatric IBD. Through melding of new technology, genomics, IBD, epidemiology and immunology, and ultimately the microbiome, the proposed research will be an outstanding platform from which I will be able to build an independent line of research.