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：
7995970
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/7995970
关键词：
Adhesions Advisory Committees Affinity Agammaglobulinaemia tyrosine kinase Allergic Disease 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 Committee Members Defect Development Dinitrophenols Disease Dominant-Negative Mutation Environment Event Faculty Gene Transduction Agent Genes Host Defense Hypersensitivity IgE In Vitro Inflammatory Integrins International Intravenous Jordan LCP2 gene Laboratories Leukocytes Life 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 Reaction Relative (related person)Research Research Personnel Residencies Residual state Resistance Retroviral Vector Rheumatoid Arthritis Rheumatology Role 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 allergic response authority career chemokine crosslink cytokine design 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

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.

该建议描述了一项为期5年的培训计划，以发展输血医学。 PI已完成大学临床病理的正式居住培训宾夕法尼亚州，现在正在扩大他在血库/输血医学和科学方面的临床技能信号转导生物学的技能。加里·科雷茨基（Gary Koretzky）博士，信号转导的国际权威生物学将指导主要研究者的科学发展。 Koretzky博士是风湿病学并拥有一位赋予病理学的捐赠椅，并为许多学生提供了指导，博士后博士学位研究员和初级教师。为了进一步促进研究者的科学发展，咨询委员会由备受推崇的医学科学家组成，包括Drs.steven L. Reiner，沃伦 S. Pear和Don L. Siegel已建立。作为输血医学的公认领导者，西格尔博士还将指导主要研究者的临床发展。拟议的研究重点是肥大细胞的信号转导，这是过敏性炎症细胞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影响并干扰挽救生命的治疗。所以，了解肥大细胞激活的机制对于输血医学特别重要，并设计新型的治疗剂以减弱肥大细胞反应，因为更新开发了用于基因疗法的细胞疗法和载体的形式。为此，该提议特别侧重于肥大细胞激活的一个重要方面，即SLP-76和其他适配器分子在 IgE介导的肥大细胞信号转导。缺乏SLP-76的小鼠在血管形成，T细胞中显示缺陷血小板和肥大细胞。鉴于导师关于SLP-76分子的专业知识，Koretzky博士实验室提供了研究SLP-76和相关分子在肥大细胞功能。具体目的包括：1）确定SLP-76和替代SLP-76-的贡献肥大细胞功能中的独立途径，2）研究桅杆中SLP-76的结构/功能关系细胞和3）检查这些分子参与肥大细胞功能中的过敏反应小鼠模型。 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。总而言之，肥大细胞在从蜂箱到生命的严重程度的过敏性疾病中起主要作用 - 威胁过敏性输血反应。该建议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轨道记录调查员的导师和咨询委员会成员，所需的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的研究设施的质量中心构成了一个理想的环境，在其中开展了该建议的培训计划。