Investigation of the Transforming Growth Factor Beta Pathway in Eosinophilic Esophagitis

嗜酸性粒细胞性食管炎转化生长因子β通路的研究

• 批准号: 9316589
• 负责人: ANTHONY L GUERRERIO
• 金额: $ 17.17万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-27 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9316589
• 关键词: Affect; Age; Allergic; Allergic inflammation; American; Amination; Amines; Antigens; Automobile Driving; Basic Science; Biochemistry; Biological Models; Biophysics; Biopsy; Bone Marrow Transplantation; Breeding; Cell Lineage; Cell physiology; Cells; Child; Childhood; Choline; Choline Deficiency; Clinical Trials; Crystallization; DNA; Data; Defect; Development; Diagnosis; Disease; Disease model; Eosinophilic Esophagitis; Epithelial Cells; Epithelium; Esophageal; Esophageal Diseases; Esophagus; Etiology; Event; Exhibits; FDA approved; FOXP3 gene; Faculty; Failure; Fellowship; Fibrosis; Five-Year Plans; Food; Food Hypersensitivity; Funding; Gastroenterology; Genes; Genetic; Genetic Predisposition to Disease; Genomics; Goals; Grant; Hematopoietic; High Prevalence; Human; Immune; Immune response; Immune system; Immunity; Immunologics; Immunology; Immunosuppression; Individual; Inflammation; Inflammatory; Inflammatory Infiltrate; Institutes; Intestines; Intravenous; Investigation; K-Series Research Career Programs; Knock-in Mouse; Knockout Mice; Knowledge; Lead; Loeys-Dietz Syndrome; Losartan; Lymphocyte; Mediating; Medical; Medicine; Mendelian disorder; Mentors; Mentorship; Metals; Methods; Molecular; Molecular Biology; Mus; Mutate; Mutation; Nutrient; Pathogenesis; Pathway interactions; Patients; Pediatrics; Pharmaceutical Preparations; Pharmacology; Phenocopy; Phenotype; Phosphorylation; Physicians; Physics; Plasma; Play; Population; Positioning Attribute; Postmenopause; Prevalence; Principal Investigator; Production; Proteins; Public Health Schools; Publications; Regulatory T-Lymphocyte; Research; Research Infrastructure; Research Personnel; Residencies; Resources; Risk; Role; Scientist; Secure; Severities; Signal Pathway; Signal Transduction; Spleen; Steroids; Surface; Syndrome; T-Lymphocyte; T-Lymphocyte Subsets; TGFBR1 gene; TGFBR2 gene; TSLP gene; Testing; Therapeutic; Therapeutic Intervention; Time; Training; Training Programs; Transforming Growth Factor beta; United States National Institutes of Health; Universities; Woman; Work; Zinc; arm; career; career development; cell type; cytokine; design; disease-causing mutation; eosinophil; experience; experimental study; gastrointestinal system; human data; immune activation; immunoreaction; interest; loss of function; mouse model; new therapeutic target; nonalcoholic steatohepatitis; novel therapeutics; oral tolerance; professor; public health relevance; receptor; research and development; response; skills; skills training; transcription factor

 DESCRIPTION (provided by applicant): This proposal is designed to provide the Principal Investigator, Anthony L. Guerrerio, with the necessary knowledge, skills, infrastructure and experience required to transition to a position as an independent researcher in the field of pediatric gastroenterology, focusing on mucosal immunology and its role in oral tolerance and the development of Eosinophilic Esophagitis (EoE). Dr. Guerrerio outlines a five-year plan to investigate the basic mechanism by which mutations in the TGFβ receptor lead to immune dysregulation and the development of EoE. This work will be performed under the mentorship of Dr. Harry C Dietz, Victor McKusick Professor of Medicine and Genetics and Investigator in the Howard Hughes Medical Institute at Johns Hopkins University. Dr. Dietz has an impressive track record of mentoring young investigators for successful careers in academic medicine, including those funded under the K award mechanism. Dr. Guerrerio also has the support of a team of extraordinary physician scientists at Johns Hopkins including Drs. Cynthia Sears and David Huso. All of these individuals have committed their time, resources, and expertise to facilitate Dr. Guerrerio's career development and research goals. In addition, the candidate will acquire additional skills and training through didactic coursework at the highly regarded Johns Hopkins Bloomberg School of Public Health. The candidate's past academic experiences underscore his commitment to academic medicine and his desire to acquire rigorous and complete scientific training. He completed a MS in physics, then entered the NIH-sponsored Medical Scientist Training Program at Johns Hopkins University and did his graduate work under the mentorship of Dr. Jeremy Berg in the Department of Molecular Biophysics. There he performed basic research investigating the molecular events that allow intracellular zinc-sensing by a metal responsive transcription factor. He also developed a method of targeting proteins to a single-stranded region of DNA, which may have therapeutic applications. He completed both a residency in Pediatrics and a fellowship in Pediatric Gastroenterology at Johns Hopkins University. During fellowship, he became interested in the role of choline, a small quaternary amine now known to be an essential nutrient for humans. He completed a small clinical trial in children with intestinal failure that revealed a high prevalenc of choline deficiency in this population, and suggested that intravenous delivery of choline may be required to replete choline in this population. This study also defined normal plasma choline percentiles by age for the first time. He also demonstrated a role for choline deficiency in the development of fibrosis in post-menopausal women with nonalcoholic steatohepatitis (NASH). Returning to the lab, Dr. Guerrerio became interested in the mucosal immune system and how inappropriate immune activation can lead to EoE. This interest crystalized around the characterization of Loeys-Dietz Syndrome (LDS), a newly described autosomal dominant disorder caused by mutations in the genes encoding the receptor subunits for TGFβ. LDS is associated with an increased risk of developing EoE and other more general food allergies. Remarkably, LDS mice also demonstrate increased Th2 inflammation, and the spontaneous development of EoE. Dr. Guerrerio joined the faculty at Johns Hopkins as an Assistant Professor in July 2009. His research experiences have afforded him with a unique background in molecular biology, biochemistry, immunology, and both human and murine models of disease. He is now poised to apply these skills, under the guidance of his mentors, to study the basic mechanisms underlying the development of EoE. The research in this proposal will focus on the role of the TGFβ pathway and its interplay between the cell types of the esophagus using LDS mice as a model system. Aims include: 1) To define the role of lymphocytes and Tregs in the development of EoE in LDS and how signaling alterations in these cells lead to inappropriate production of Th2 cytokines, 2) Investigate the role of epithelia cells and other nonhematopoietic cells in the development of EoE in LDS, and 3) Define the signaling defect in lymphocytes carrying the LDS mutation and test whether pharmacologic inhibition of TGFβ signaling mitigates the EoE phenotype. The scientific training obtained through this grant will lead to publications, data, and experience that will enable the candidate t secure independent NIH funding within the next 4-5 years and establish himself as an independent physician scientist.

 描述（由申请人提供）：本提案旨在为主要研究者Anthony L. Guerrerio拥有必要的知识，技能，基础设施和经验，可以过渡到儿科胃肠病学领域的独立研究人员，专注于粘膜免疫学及其在口服耐受性和嗜酸性食管炎（EoE）发展中的作用。Guerrerio博士概述了一项五年计划，以研究TGFβ受体突变导致免疫失调和EoE发展的基本机制。这项工作将在约翰霍普金斯大学霍华德休斯医学研究所的维克托麦库斯克医学和遗传学教授和研究员哈里C迪茨博士的指导下进行。Dietz博士在指导年轻研究人员在学术医学领域取得成功方面有着令人印象深刻的记录，包括那些在K奖机制下资助的研究人员。Guerrerio博士还得到了约翰斯大学一组杰出的内科科学家的支持 霍普金斯包括辛西娅·西尔斯和大卫·胡索医生。所有这些人都投入了他们的时间，资源和专业知识，以促进Guerrerio博士的职业发展和研究目标。此外，候选人将获得额外的技能和培训，通过教学课程在高度重视约翰霍普金斯彭博公共卫生学院。 候选人过去的学术经验强调了他对学术医学的承诺， 渴望获得严格和完整的科学训练。他完成了物理学硕士学位，然后进入美国国立卫生研究院赞助的约翰霍普金斯大学医学科学家培训计划，并在分子生物物理学系杰里米贝格博士的指导下完成了研究生工作。在那里，他进行了基础研究，调查允许金属响应转录因子的细胞内锌感应的分子事件。他还开发了一种将蛋白质靶向DNA单链区域的方法，该方法可能具有治疗应用。他在约翰霍普金斯大学完成了儿科住院医师和儿科胃肠病学奖学金。在研究期间，他对胆碱的作用产生了兴趣，胆碱是一种小的季胺，现在已知是人类的必需营养素。他完成了一项针对肠衰竭儿童的小型临床试验，结果显示这一人群中胆碱缺乏症的患病率很高，并建议静脉注射胆碱可能需要补充这一人群中的胆碱。这项研究还首次根据年龄定义了正常的血浆胆碱水平。他还证明了胆碱缺乏在患有非酒精性脂肪性肝炎（NASH）的绝经后妇女纤维化发展中的作用。回到实验室，Guerrerio博士开始对粘膜免疫系统以及不适当的免疫激活如何导致EoE感兴趣。这种兴趣围绕Loeys-Dietz综合征（LDS）的特征而结晶，LDS是一种新描述的常染色体显性遗传疾病，由编码TGFβ受体亚基的基因突变引起。LDS与风险增加有关 出现Eoe和其他更一般的食物过敏。值得注意的是，LDS小鼠还表现出增加的Th 2炎症和EoE的自发发展。Guerrerio博士于2009年7月加入约翰霍普金斯大学担任助理教授。他的研究经验使他在分子生物学，生物化学，免疫学以及人类和小鼠疾病模型方面具有独特的背景。他现在准备在导师的指导下，运用这些技能来研究EoE发展的基本机制。 本提案中的研究将集中在TGFβ通路的作用及其与肿瘤细胞之间的相互作用。 细胞类型的食管使用LDS小鼠作为模型系统。目标包括：1）确定 淋巴细胞和TGF β在LDS EoE发生中的作用，以及这些细胞中的信号传导改变如何导致Th 2细胞因子的不适当产生，2）研究上皮细胞和其他非造血细胞在LDS EoE发生中的作用，3）确定携带LDS突变的淋巴细胞中的信号传导缺陷，并测试TGFβ信号传导的药理学抑制是否减轻EoE表型。通过这项资助获得的科学培训将导致出版物，数据和经验，使候选人能够在未来4-5年内获得独立的NIH资助，并成为独立的医生科学家。