Very Early-onset inflammatory bowel disease

极早发性炎症性肠病

• 批准号: 8766777
• 负责人: Judith Rachel Kelsen
• 金额: $ 17.32万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8766777
• 关键词: 6 year old; Address; Adult; Adverse reactions; Age; Algorithms; Anti-Tumor Necrosis Factor Therapy; Area; Autoimmune Process; Basic Science; Bioinformatics; Caring; Child; Child Care; Childhood; Clinical; Clinical Investigator; Clinical Research; Collaborations; Complex; Consensus; Control Groups; Custom; DNA; Data; Data Analyses; Development; Diagnosis; Disease; Doctor of Philosophy; Environment; Epidemiology; Evaluation; Exposure to; Faculty; Failure; Family; Fellowship; Future; Gastroenterology; Gastrointestinal tract structure; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Research; Genomics; Genotype; Goals; Growth; Health; Hepatology; Human; Immune; Immune response; Immunologic Deficiency Syndromes; Immunologics; Immunology; Incidence; Inflammatory; Inflammatory Bowel Diseases; Institutes; Instruction; Investigator-Initiated Research; K-Series Research Career Programs; Lead; Light; Link; Logistic Models; Medicine; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Methods; Microbiology; Modeling; Molecular Abnormality; Mutation; Natural History; Older Population; Operative Surgical Procedures; Patients; Pediatric Hospitals; Penetrance; Pennsylvania; Pharmaceutical Preparations; Philadelphia; Pilot Projects; Population; Population Analysis; Preceptorship; Protocols documentation; Publications; Refractory; Registries; Reporting; Research; Research Design; Research Ethics; Research Personnel; Resources; Risk; Role; Severities; Severity of illness; Shapes; Site; Societies; Stem cell transplant; Structure; Subgroup; Symptoms; TNF gene; Testing; Therapeutic; Time; Training; Training Support; Translational Research; Tumor Necrosis Factor-alpha; Universities; Variant; Writing; career; career development; clinical phenotype; cohort; conventional therapy; data modeling; density; design; disease phenotype; early onset; exome sequencing; experience; genetic pedigree; genetic variant; gut microbiota; high risk; infliximab; interdisciplinary approach; interest; medical schools; microbiome; new technology; novel; nutrition; older patient; oral microbiome; patient oriented; patient oriented research; patient population; patient registry; predictive modeling; professor; programs; prospective; rare variant; research study; response; skills; translational study

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.

描述（由应用程序提供）：我目前是费城儿童医院（CHOP）的胃肠病学，肝病学和营养部的助理教授，他于2009年6月在CHOP上完成了胃肠病学研究金。宾夕法尼亚州（UPENN）医学院。我现在正在申请一项受过指导的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，成为转化研究的独立研究者，重点是早期发作的炎症性肠病（VEO-IBD）。这项培训将使我有机会获得有价值的经验，以将基础科学进步与临床表型联系起来，以在评估和治疗这些孩子的评估和治疗中产生一种方法。我的短期目标是在研究我们独特的VEO-IBD患者人群的设计，进行和分析方面获得额外的培训和经验。我的长期目标是领导该队列中的前瞻性翻译研究，协作和整合基因组学，微生物学和免疫学以对这些患者的个性化治疗。在团契毕业后，在我的导师的指导下，我领导了一项关于小儿CD口腔微生物组的研究。这使我能够发展基准研究技能，并开始培养研究设计和数据分析方面的技能。与这个主题一致 在我的精神上，我在MD上写了一篇关于“肠道菌群，环境和现代社会的疾病和“ IBD和微生物组”的评论。在这段时间里，我对IBD非常年幼的孩子产生了兴趣，这是由于疾病的严重表现以及对我的贡献不足的贡献，这些疾病的贡献是我的努力。我对英夫利昔单抗治疗的反应不佳。在该队列中，以基因组，微生物组，免疫学和表型分析的素食性分析为中心。因此，我和我的导师一起设计了本次K-23中提出的指导的科学和教育计划，包括（1）在我的研究兴趣方面的正式教学教学，例如基因组学和免疫学（2）等同于研究培养基（2）等同于与计算基因组学，表演性和不合理学（3）领域的高级师资（3）培训（3）培训（3）的高级教师（3）遗传研究的伦理（5）在本应用程序中描述的研究计划的完成（6）Upenn和Chop的其他发展活动。在高级教职员工的紧密心态和指导下，我将进行越来越独立的临床研究。在该K23奖的后期，我将提交研究人员发起的研究的申请，例如R01S。我职业发展的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博士博士是该研究职业发展奖的主要赞助商。该提议如下所述。在不到6岁的儿童中发生的炎症性肠病被称为veo-ibd。与成年人相比，患有VEO-IBD的儿童通常具有更严重的症状和更大程度的胃肠道参与。与老年患者相比，疾病和年轻年龄的严重程度表明，免疫响应的遗传和失调更明显。例如，在几名严重的素食性素食患者中已经鉴定出IL10R基因中的变体，现在已经指出了干细胞移植而不是抗TNFα疗法的患者。但是，大多数VEO-IBD病例的原因尚不清楚。这是对这些和其他免疫缺陷的鉴定对于用于治疗素食人群的临床算法的发展至关重要。 CHOP中看到的VEO-IBD患者的人口为解决有关VEO-IBD的临床过程的实质性问题提供了机会，并确定患有特定遗传异常的患者的亚组。该提案的目的是检验总体假设，即veo-ibd代表了一种独特的IBD形式，具有严重，侵略性疾病的高风险，并且是由一组与后来发作的IBD相比，由一组独特的遗传变异引起的。如果成功，该提案将对EO-IBD儿童的诊断和治疗产生重大影响，并且可能会阐明IBD的原因。我们的具体目标是：1）确定VEO-IBD是否与更严重的短期疾病病程相关，该病程定义为需要早期手术或难治性生长衰竭，而不是后来的儿科IBD； 2）定义已知的IBD基因座在VEO-IBD中的作用并确定新的因果突变； 3）确定小儿IBD早期手术的遗传和表型预测指标。通过融合新技术，基因组学，IBD，流行病学和免疫学以及最终的微生物组，拟议的研究将是一个杰出的平台，我将能够从中建立独立的研究系列。