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：
7352737
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/7352737
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 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

This proposal describes a 5-year training program for the development of an academic career in Transfusion Medicine. The PI 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.

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。 PI 已在大学完成临床病理学的正式住院医师培训宾夕法尼亚州的，现在正在扩展他在血库/输血医学和科学方面的临床技能信号转导生物学技能。国际信号转导领域权威Gary Koretzky博士生物学，将指导首席研究员的科学发展。 Koretzky 博士是风湿病学并担任病理学教授，指导了众多学生、博士后研究员和初级教员。为进一步促进研究者的科学发展，顾问委员会由备受尊敬的医学科学家组成，包括 Drs. 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主要研究者的临床开发。拟议的研究重点是肥大细胞的信号转导，肥大细胞是过敏症中的关键炎症细胞哮喘、过敏反应和特应性皮炎等反应。对输血的过敏反应是常见的不良反应并干扰救生治疗的实施。所以，了解肥大细胞激活的机制对于输血医学特别重要，随着新技术的出现，设计新的疗法来减弱肥大细胞反应将变得尤为重要开发了细胞疗法和基因疗法载体的形式。为此，本提案特重点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。缺乏SLP-76的小鼠显示出血管形成、T细胞、血小板和肥大细胞。鉴于导师在 SLP-76 分子方面的专业知识，Koretzky 博士的实验室提供了一个理想的环境来研究 SLP-76 和相关分子在肥大细胞功能。具体目标包括：1) 确定 SLP-76 和替代 SLP-76 的贡献- 肥大细胞功能的独立通路，2）研究肥大细胞中SLP-76的结构/功能关系细胞，3) 检查这些分子在过敏反应小鼠肥大细胞功能中的参与情况模型。 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生命- 威胁过敏性输血反应。该提案旨在剖析分子机制参与肥大细胞信号转导。校长的智力实力和学术记录研究者的导师和咨询委员会成员，所需方法的可用专业知识研究信号转导以及宾夕法尼亚大学医学院研究设施的质量中心提供了进行拟议培训计划的理想环境。