The role of adapter molecules in mast cell function

接头分子在肥大细胞功能中的作用

基本信息

批准号：
7176476
负责人：
Taku Kambayashi
金额：
$ 13.3万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-02-09 至 2011-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7176476
关键词：
Adhesions Advisory Committees Affinity Agammaglobulinaemia tyrosine kinase Allergic Anaphylaxis Antibodies Antigens Arachidonic Acids Asthma Atopic Dermatitis Attenuated Autoimmune Diseases Binding Biochemical Biological Assay Biology Blood Banks Blood Platelets Blood Vessels Bone Marrow Cell Communication Cell physiology Cells Clinical Clinical Pathology Clinical Skills Defect Development Dinitrophenols Disease Disruption Dominant-Negative Mutation Environment Event Faculty Genes Host Defense Hypersensitivity IgE In Vitro Inflammatory Integrins International Intravenous Jordan Laboratories Leukocytes Life Localized Mediating Mediator of activation protein Medical Medical center Medicine Membrane Mentors Methods Microscopy Modeling Molecular Multiple Sclerosis Mus Mutation N-terminal Parasites Pathology Pathway interactions Pear Pennsylvania Peptide Fragments Peptides Phenotype Phenylalanine Phosphoproteins Phosphorylation Play Postdoctoral Fellow Principal Investigator Production Program Development Proline-Rich Domain Property Proteins Range Reaction Relative (related person)Research Research Personnel Residencies Residual state Resistance Retroviral Vector Rheumatoid Arthritis Rheumatology Role Role playing therapy Scaffolding Protein Scientist Severities Signal Pathway Signal Transduction Signaling Molecule Structure-Activity Relationship Students T-Lymphocyte Testing Therapeutic Agents Training Training Programs Transfusion Tyrosine Universities Urticaria abstracting authority career chemokine crosslink cytokine design gene therapy in vivo inhibitor/antagonist mast cell member mouse model novel therapeutics prevent programs receptor binding research facility research study response skills src Homology Region 2 Domain vector

项目摘要

DESCRIPTION (provided by applicant): This proposal describes a 5-year training program for the development of an academic career in Transfusion Medicine. The Principal Investigator has completed formal residency training in Clinical Pathology at the University of Pennsylvania and is now expanding his clinical skills in blood banking/transfusion medicine and scientific skills in signal transduction biology. Dr. Gary Koretzky, an international authority in signal transduction biology, will mentor the principal investigator's scientific development. Dr. Koretzky is the Chief of Rheumatology and holds an endowed chair in pathology having mentored numerous students, post-doctoral fellows, and junior faculty members. To further promote the investigator's scientific development, an Advisory Committee comprising highly regarded medical scientists including Drs. Steven L. Reiner, Warren S. Pear, and Don L. Siegel has been established. As a recognized leader in transfusion medicine, Dr. Siegel will also mentor the principal investigator's clinical development. The proposed research focuses on signal transduction of the mast cell, a key inflammatory cell in allergic responses such as asthma, anaphylaxis, and atopic dermatitis. Allergic responses to transfusion are a common untoward effect and interfere with the administration of life-saving therapy. Therefore, understanding the mechanisms of mast cell activation is of particular importance to transfusion medicine, and designing novel therapeutics to attenuate mast cell responses will be especially important as newer forms of cellular therapies and vectors for gene therapy are developed. To this end, this proposal specifically focuses on an important aspect of mast cell activation, i.e. the role of SLP-76 and other adaptor molecules in IgE-mediated mast cell signal transduction. Mice lacking SLP-76 show defects in vascular formation, T cells, platelets, and mast cells. Given the Mentor's expertise regarding the SLP-76 molecule, Dr. Koretzky's laboratory provides an ideal setting to study the precise roles played by SLP-76 and related molecules in mast cell function. Specific Aims include: 1) determining the contribution of SLP-76 and alternative SLP-76- independent pathways in mast cell function, 2) studying the structure/function relationship of SLP-76 in mast cells, and 3) examining the involvement of these molecules in mast cell function in an anaphylaxis mouse model. The utility of an SLP-76 inhibitor as a therapeutic agent will be tested in the anaphylaxis model. In summary, mast cells play a major role in allergic diseases ranging in severity from hives to life threatening anaphylactic transfusion reactions. This proposal aims to dissect the molecular mechanisms involved in mast cell signal transduction. The intellectual strength and academic track-record of the principal investigator's Mentor and Advisory Committee members, the available expertise in methods required to study signal transduction, and the quality of the research facilities at the University of Pennsylvania Medical Center comprise an ideal environment in which to conduct this proposed training program. (End of Abstract)

描述（由申请人提供）：该提案描述了一个为期 5 年的学术职业发展培训计划输血医学。首席研究员已在宾夕法尼亚大学完成了临床病理学的正式住院医师培训，目前正在扩展其在血库/输血医学方面的临床技能以及信号转导生物学方面的科学技能。信号转导生物学领域的国际权威 Gary Koretzky 博士将指导首席研究员的科学发展。 Koretzky 博士是风湿病科主任，并担任病理学教授，指导过众多学生、博士后研究员和初级教员。为了进一步促进研究者的科学发展，咨询委员会由包括 Drs. 在内的备受尊敬的医学科学家组成。 Steven L. Reiner、Warren S. Pear 和 Don L. Siegel 已成立。作为输血医学领域公认的领导者，西格尔博士还将指导首席研究员的临床开发。拟议的研究重点是肥大细胞的信号转导，肥大细胞是哮喘、过敏反应和特应性皮炎等过敏反应中的关键炎症细胞。对输血的过敏反应是一种常见的不良反应，并且会干扰挽救生命的治疗的实施。因此，了解肥大细胞激活的机制对于输血医学特别重要，并且随着更新形式的细胞疗法和基因治疗载体的开发，设计新的疗法来减弱肥大细胞反应将尤其重要。为此，该提案特别关注肥大细胞激活的一个重要方面，即SLP-76和其他衔接分子在IgE介导的肥大细胞信号转导中的作用。缺乏SLP-76的小鼠在血管形成、T细胞、血小板和肥大细胞方面表现出缺陷。鉴于导师在 SLP-76 分子方面的专业知识，Koretzky 博士的实验室为研究 SLP-76 和相关分子在肥大细胞功能中所发挥的精确作用提供了理想的环境。具体目标包括：1) 确定 SLP-76 和替代 SLP-76 独立途径对肥大细胞功能的贡献，2) 研究肥大细胞中 SLP-76 的结构/功能关系，以及 3) 检查这些因素的参与过敏反应小鼠模型中肥大细胞功能的分子。 SLP-76 抑制剂作为治疗剂的效用将在过敏反应模型中进行测试。总之，肥大细胞在过敏性疾病中发挥着重要作用，其严重程度从荨麻疹到危及生命的过敏性输血反应。该提案旨在剖析肥大细胞信号转导涉及的分子机制。主要研究者的导师和咨询委员会成员的智力实力和学术记录、研究信号转导所需方法的现有专业知识以及宾夕法尼亚大学医学中心的研究设施的质量构成了一个理想的环境，执行本拟议的培训计划。（摘要完）