Very Early-onset inflammatory bowel disease

简介(由申请人提供)：我目前是费城儿童医院(CHOP)胃肠病学、肝病和营养科的助理教授，于2009年6月在CHOP完成胃肠病学奖学金。为了获得翻译研究方面的培训，我在宾夕法尼亚大学(UPenn)医学院翻译和治疗医学研究所(ITMAT)完成了翻译研究硕士(MTR)学位。我现在正在申请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)的翻译研究的独立研究员。这次培训将使我有机会获得宝贵的经验，将基础科学的进步与临床表型联系起来，进行以患者为导向的研究，从而为这些儿童的评估和治疗提供一种方法。我的短期目标是在设计、实施和分析以患者为导向的转化性研究方面获得更多的培训和经验，研究我们独特的VEO-IBD患者群体。我的长期目标是在这个队列中领导前瞻性的翻译研究，合作并整合基因组学、微生物学和免疫学，为这些患者提供个性化的治疗。毕业后，在导师的指导下，我领导了一项关于儿科CD中口腔微生物组的研究。这让我发展了长椅研究的技能，并开始培养研究设计和数据分析的技能。为配合这一主题， 我和我的导师，医学博士加里·吴一起写了一篇关于“肠道微生物区系、环境和现代社会的疾病”以及“IBD和微生物组”的评论。在这段时间里，我开始对患有IBD的非常年幼的儿童感兴趣，这既是因为他们严重的疾病表现，也是因为他们在护理方面缺乏共识。除了我的目标是研究这些孩子的微生物组外，我还对了解他们疾病的强大基因贡献感兴趣。我对他们对英夫利昔单抗治疗反应不佳的评估开始解决这个问题，数据已经提交发表。我最近的试点项目利用整个外显子组测序来检测疾病的新的和罕见的原因变异，进一步探索了这个问题，并为这个项目生成了初步数据。这些经历帮助我形成了这个提议的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一队列的最佳护理，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，我和我的导师们一起设计了K-23课程中提出的指导性科学和教育计划，包括(1)与我的研究兴趣相关的领域的正式教学指导，如基因组学和免疫学(2)在计算基因组学、流行病学和免疫学方面与高级教员的指导研究指导(3)与相关领域的专家教员进行有组织的合作(4)在负责任的研究和基因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的其他开发活动。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奖的最后几年，我将提交研究人员发起的研究申请，例如R01。我职业发展中不可或缺的一部分将是高级临床研究人员提供的指导。Marcella Devoto博士是这项研究职业发展奖的主要赞助商。该提案如下所述。炎症性肠病发生在6岁以下的儿童，称为VEO-IBD。患有VEO-IBD的儿童通常比成年人有更严重的症状和更大程度的胃肠道受累。疾病的严重程度和表现的年轻年龄表明，与老年患者相比，遗传和免疫调节失调的反应更加明显。例如，IL10R基因的变异已经在几个严重的VEO-IBD患者中被发现，对于这些患者，现在建议进行干细胞移植，而不是抗肿瘤坏死因子α治疗。然而，大多数VEO-IBD病例的病因尚不清楚。因此，识别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上看到的VEO-IBD患者群体提供了一个机会来解决关于VEO-IBD临床病程的实质性问题，并识别具有特定遗传异常的患者亚群。这项提议的目标是检验总体假设，即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，并且是由一组与晚发型IBD不同的遗传变异引起的。如果成功，这项建议将对EO-IBD儿童的诊断和治疗产生重大影响，并可能揭示IBD的一般原因。我们的具体目标是：1)确定VEO-IBD是否与比起病较晚的儿童IBD更严重的短期病程(定义为需要早期手术或难治性生长障碍)有关；2)确定已知IBD基因座在VEO-IBD中的作用并识别新的因果突变；3)确定儿童IBD早期手术的那些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，最终融合微生物组，拟议的研究将成为一个杰出的平台，我将能够在此基础上建立一条独立的研究路线。

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.