Investigation of the Role of TGF Beta in TH2-Mediated Disease

TGF Beta 在 TH2 介导的疾病中的作用的研究

基本信息

批准号：
8414878
负责人：
Pamela Ann Guerrerio
金额：
$ 13.43万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-01-01 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8414878
关键词：
Affect Age Allergic Disease Allergy to peanuts Antigens Aortic Aneurysm Asthma Attenuated Basic Science Basophils Biochemical Biological Assay Biological Models Bone Marrow Cardiovascular system Cell Count Cellular Assay Child Clinical Commit Data Defect Dendritic Cells Development Disease Disease Pathway Disease model Eczema Effector Cell Eosinophilia Eosinophilic Esophagitis Etiology Event Exclusion Exhibits FDA approved Faculty Fellowship Five-Year Plans Food Hypersensitivity Foundations Funding Gene Expression Genetic Genetic Medicine Genomics Goals Grant High Prevalence Homeostasis Human Hypersensitivity IgE Immune Immune system Immunity Immunohistochemistry Immunologics Immunology In Vitro Individual Institutes Investigation K-Series Research Career Programs Knock-in Mouse Knowledge Lead Loeys-Dietz Syndrome Losartan Lymphocyte Mediating Medical Medicine Mentors Mentorship Modeling Molecular Biology Mus Mutate Mutation Nonsense-Mediated Decay Pathogenesis Pathway interactions Patients Pediatrics Peripheral Pharmaceutical Preparations Phenotype Physicians Plasma Population Positioning Attribute Predisposition Prevalence Principal Investigator Process Public Health Schools Publications RNA RNA Stability Regulatory T-Lymphocyte Research Research Personnel Residencies Resources Role Schools Scientist Secure Series Severities Signal Pathway Signal Transduction Skeletal Development Syndrome T-Cell Development T-Lymphocyte TGFBR1 gene TGFBR2 gene Testing Therapeutic Thymus Gland Time Training Training Programs Transforming Growth Factor beta United States National Institutes of Health Universities Wood material Work base career career development cell type cohort craniofacial cytokine design effective therapy experience food environment human subject in vivo in vivo Model interest mRNA Decay mouse model novel peripheral blood professor receptor research and development response skills skills training

Affect Age Allergic Disease Allergy to peanuts Antigens Aortic Aneurysm Asthma Attenuated Basic Science Basophils Biochemical Biological Assay Biological Models Bone Marrow Cardiovascular system Cell Count Cellular Assay Child Clinical Commit Data Defect Dendritic Cells Development Disease Disease Pathway Disease model Eczema Effector Cell Eosinophilia Eosinophilic Esophagitis Etiology Event Exclusion Exhibits FDA approved Faculty Fellowship Five-Year Plans Food Hypersensitivity Foundations Funding Gene Expression Genetic Genetic Medicine Genomics Goals Grant High Prevalence Homeostasis Human Hypersensitivity IgE Immune Immune system Immunity Immunohistochemistry Immunologics Immunology In Vitro Individual Institutes Investigation K-Series Research Career Programs Knock-in Mouse Knowledge Lead Loeys-Dietz Syndrome Losartan Lymphocyte Mediating Medical Medicine Mentors Mentorship Modeling Molecular Biology Mus Mutate Mutation Nonsense-Mediated Decay Pathogenesis Pathway interactions Patients Pediatrics Peripheral Pharmaceutical Preparations Phenotype Physicians Plasma Population Positioning Attribute Predisposition Prevalence Principal Investigator Process Public Health Schools Publications RNA RNA Stability Regulatory T-Lymphocyte Research Research Personnel Residencies Resources Role Schools Scientist Secure Series Severities Signal Pathway Signal Transduction Skeletal Development Syndrome T-Cell Development T-Lymphocyte TGFBR1 gene TGFBR2 gene Testing Therapeutic Thymus Gland Time Training Training Programs Transforming Growth Factor beta United States National Institutes of Health Universities Wood material Work base career career development cell type cohort craniofacial cytokine design effective therapy experience food environment human subject in vivo in vivo Model interest mRNA Decay mouse model novel peripheral blood professor receptor research and development response skills skills training

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项目摘要

DESCRIPTION (provided by applicant):This proposal is designed to provide the Principal Investigator, Pamela A. Guerrerio, with the necessary knowledge, skills, and experience required to transition to a position as an independent researcher in the field of allergy and immunology. Dr. Guerrerio outlines a five-year plan to investigate the basic mechanism by which TGF-¿ regulates immunity, and specifically how it participates in the pathogenesis of Th2-mediated disease. This work will be performed under the mentorship of Dr. Harry C Dietz, Victor McKusick Professor of Medicine and Genetics and an 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 Dr. Jonathan Powell, Dr. Zhou Zhu, and Dr. Robert Wood. 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 her commitment to academic medicine and her desire to acquire rigorous and complete scientific training. She completed the NIH-sponsored Medical Scientist Training Program at Johns Hopkins University and did her graduate work under the mentorship of Dr. Dietz. During graduate school, she performed very basic research in the mechanisms of RNA stability, and discovered a novel mRNA decay pathway, termed nonstop decay, that appears to be a new mechanism to regulate gene expression. Using murine models, she also demonstrated how another RNA surveillance mechanism, nonsense mediated decay, is required for normal lymphocyte development and proper allelic exclusion. She completed both a residency in Pediatrics and a fellowship in Allergy and Immunology at Johns Hopkins University. During fellowship, she became interested in food allergy and mucosal tolerance and has led several studies to investigate the role of human dendritic cells and basophils in the pathogenesis of food allergy. Dr. Guerrerio joined the faculty at Johns Hopkins as an Assistant Professor in July 2009. Her research experiences have afforded her with a unique background in molecular biology, genetics, immunology, and both human and murine models of disease. She is now poised to apply these skills, under the guidance of her mentors, to study the basic immunologic mechanisms that lead to loss of tolerance and development of food allergy. The research in this proposal will focus on the role of TGF-¿ in the development of allergic disease. The scientific approach will involve the study of Loeys-Dietz syndrome (LDS), a newly described autosomal dominant disorder caused by mutations in the TGF-¿ receptors, as a model system. LDS appears to be the first Mendelian disorder associated with the development of food allergy and eosinophilic esophagitis, and offers an unparalleled opportunity to study the role of TGF-¿ in the human immune system. Specific Aims include: I): Investigate the signaling alterations in human lymphocytes caused by LDS mutations and how they lead to increased Th2 effector responses II): Define the biochemical and cellular events leading to the increased propensity for Th2-mediated disease in LDS mice, and how this process can be mitigated by pharmacologic inhibition of TGF-¿ signaling. The scientific training obtained through this grant will lead to publications, data, and experience that will enable the candidate to secure independent NIH funding within the next 3-4 years and establish herself an independent physician scientist. Food allergy and eosinophilic esophagitis have become increasingly common clinical problems for which there is no known cure. We have recently identified the TGF-¿ pathway to be specifically involved in the development of these disorders. In this proposal, we will seek to understand the mechanism by which alterations in TGF-¿ signaling predispose to allergic disease, and how these pathways might be manipulated for therapeutic benefit.

描述（由应用程序提供）：该提案旨在为主要研究人员Pamela A. Guerrerio提供过渡到过敏和免疫学领域的独立研究人员所需的必要知识，技能和经验。 Guerrerio博士概述了一项为期五年的计划，以调查TGF-调节免疫力的基本机制，特别是它如何参与Th2介导的疾病的发病机理。这项工作将在约翰·霍普金斯大学（Johns Hopkins University）的霍华德·休斯医学院（Howard Hughes Hughes Institute）的Victor McKusick医学与遗传学教授Harry C Dietz博士的心态下进行。 Dietz博士在学术医学领域成功职业的年轻研究人员有一个令人印象深刻的记录，包括根据K奖励机制资助的人。 Guerrerio博士还得到了约翰·霍普金斯（Johns Hopkins）的一支非凡的物理科学家团队的支持，包括乔纳森·鲍威尔（Jonathan Powell）博士，朱朱（Zhou Zhu）博士和罗伯特·伍德（Robert Wood）博士。所有这些人都付出了时间，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，候选人将通过备受推崇的约翰·霍普金斯彭博公共卫生学院的教学课程获得其他技能和培训。候选人过去的学术经历强调了她对学术医学的承诺，以及她渴望获得严格而完整的科学培训的愿望。她在约翰·霍普金斯大学（Johns Hopkins University）完成了NIH赞助的医学科学家培训计划，并在Dietz博士的心态下完成了研究生工作。在研究生院期间，她在RNA稳定性的机制方面进行了非常基础的研究，并发现了一种新型的mRNA衰变途径，称为不间断衰减，这似乎是调节基因表达的新机制。她使用鼠模型，还证明了正常淋巴细胞发育和适当的等位基因排除需要另一种RNA监测机制，废话介导的衰减。她在约翰·霍普金斯大学（Johns Hopkins University）完成了儿科居住和过敏和免疫学研究金的居住。在奖学金期间，她在食物过敏和粘膜耐受性方面变得有趣，并导致了几项研究，研究了人树突状细胞和嗜碱性粒细胞在食物过敏的发病机理中的作用。 Guerrerio博士于2009年7月加入Johns Hopkins的教职员工。她的研究经验为她提供了分子生物学，遗传学，免疫学以及人类疾病模型的独特背景。现在，在导师的指导下，她被毒死了这些技能，以研究导致食物过敏的耐受性和发展的基本免疫机制。该提案中的研究将集中于TGF- - 在过敏性疾病发展中的作用。科学方法将涉及对Loeys-Dietz综合征（LDS）的研究，Loeys-Dietz综合征是一种新描述的常染色体显性疾病，由TGF-€接收器中的突变引起，作为模型系统。 LD似乎是与食物过敏和嗜酸性食管炎的发展相关的第一种Mendelian疾病，并且提供了无与伦比的机会，可以研究TGF-€特定目的的作用：i）：i）：研究人类淋巴细胞的信号改变因LDS突变引起的人体淋巴细胞的变化以及对TH2效应的促进型的增长症状ii）：ii ii）：ii ii）：ii ii）：ii ii）ii ii）：ii）ii ii）：ii）ii ii）： LDS小鼠的Th2介导的疾病，以及如何通过TGF- - 信号传导的药物抑制来减轻该过程。通过这笔赠款获得的科学培训将导致出版物，数据和经验，这将使候选人能够在未来3 - 4年内获得独立的NIH资金，并确立自己的独立物理科学家。食物过敏和嗜酸性静脉炎已成为越来越常见的临床问题，尚无已知的治愈方法。我们最近已经确定了TGF- - 途径专门参与这些疾病的发展。在此提案中，我们将寻求了解TGF-ood传导易感性疾病的改变的机制，以及如何操纵这些途径以获得治疗益处。