Regulation of Mast Cell Development and Function

肥大细胞发育和功能的调节

基本信息

批准号：
7388992
负责人：
Stephen Joseph Galli
金额：
$ 41.12万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1986
资助国家：
美国
起止时间：
1986-09-01 至 2011-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7388992
关键词：
1-Phosphatidylinositol 3-Kinase 2,4-Dinitrophenol 5-(6)-carboxyfluorescein diacetate succinimidyl ester Abbreviations Accounting Address Affect Affinity Allergic Anaphylaxis Antibodies Antigens Atopic Dermatitis Attention Bone Marrow Bromodeoxyuridine Cell Degranulation Cell Survival Cell secretion Chromosomes, Human, Pair 10 Chymase Class Coupling Cues Cyclin-Dependent Kinases Dermal Development Disease Economics Effector Cell Elements Endothelin-1 Esters Exhibits Extracellular Signal Regulated Kinases Extrinsic asthma Fetal Liver Glutathione S-Transferase Goals Green Fluorescent Proteins Guanine Nucleotide Exchange Factors Health Systems Agencies Hexosaminidases Histamine Histocytochemistry Homologous Gene Human IgE IgE Receptors Immune response Immunohistochemistry In Vitro Individual Inflammation Inflammatory Interleukin-3 Interleukins Iodine-131 Human Serum Albumin Leukotrienes Lipids MEKs Mediator of activation protein Mitogen-Activated Protein Kinases Molecular Monoclonal Antibodies Mus Mutation Nucleotides Numbers PTEN gene Passive Cutaneous Anaphylaxis Patients Peritoneal Phenotype Phosphotransferases Propidium Diiodide Prostaglandins Prostaglandins D Proteins Proto-Oncogene Protein c-kit Rattus Recombinants Regulation Reporting Rhinitis Role Serine Serum Serum Albumin Signal Pathway Signal Transduction Skin Stem Cell Factor Structure TNF gene Tissues Toll-like receptors Tumor Necrosis Factor-alpha Tumor Necrosis Factors Ubiquitin Ubiquitination Vacuolar Protein Sorting Venous Work Zinc Fingers beta-n-acetylhexosaminidase burden of illness cost cytokine embryonic stem cell human TNF protein in vivo mast cell mutant novel therapeutics phosphatidylinositol 3,4,5-triphosphate receptor response subcutaneous tensin ubiquitin ligase

项目摘要

Mast cells (MCs) are major effector cells in IgE antibody-dependent allergic disorders, such as anaphylaxis, allergic rhinitis and atopic asthma, which account for a very large burden of illness and economic costs in the developed world. MCsare also critical for the optimal expression of certain innate immune responses. While much attention has been focused on the elements which positively regulate the IgE- and specific antigen (Ag)-dependent secretion of pro-inflammatory mediators and cytokines from MCs, the molecular mechanisms which can suppress the magnitude and/or duration of such responses have been less studied. We recently reported that RabGEFI (Rajb guanine nucleotide exchange factor 1.) can negatively regulate Ras-dependent signaling pathways, and the secretion of all three classes of mediators (pre-formed, lipid and cytokine), in MCs stimulated with IgE and specific Ag. More recently, we found that RabGEFI also importantly regulates responses in MCs which are elicited by the major survival, developmental and proliferation factor for MCs, SCF (stem cell factor, the c-Kit ligand). Notably, our Rabgefl^' mice exhibit severe inflammation of the skin associated with increased numbers of MCs, evidence of dermal MC degranulation (i.e., "activation"), and increased levels of histamine and IgE in the serum. The central questions which we now wish to address are: By what molecular mechanisms does RabGEFI influence MC development, activation and function, and to what extent might these actions of RabGEFI on MCs account for some of the dramatic phenotypic abnormalities observed in Rabgefl^'mice? In Aim 1. we will investigate how RabGEFI, and its individual functional domains, can negatively regulate mouse MC activation induced by signaling via FceRI or c-Kit (the SCF receptor) in vitro or in vivo, and will identify and characterize RabGEFI-interacting proteins and their downstream effectors in MCswhich have been activated via these receptors. In Aim 2. we will define the mechanisms by which RabGEFI can regulate the survival, development, phenotype & proliferation of MCs in vitro and in vivo. The in vivo studies will take advantage of our ability to transfer in wfro-derived MCs which lack, or express mutant forms of, RabGEFI into the tissues of c-kit mutant, Kitw/w~v or Kit"-3¿"'*" genetically MC-deficient mice (which express wild type RabGEFI). We thus can study the effects of RabGEFI on MCs in mice in which only the MCs lack, or express mutant forms of, RabGEFI. Elucidating how RabGEFI negatively regulates FceRI- or c-Kit-dependent signaling in MCs will increase our understanding of the regulation of MC activation and development, which is the long-term goal of this project. Such work also may help in the development of new therapeutic approaches for the alleviation of diseases, such as asthma and atopic dermatitis, which are associated with IgE-dependent MC activation and, in many patients, with increased numbers of MCs in the affected tissues.

肥大细胞（MC）是IgE抗体依赖性过敏性疾病（例如过敏反应）中的主要效应细胞过敏性鼻炎和特征性哮喘，这是疾病和经济成本的大量燃烧发达世界。 McSare对于某些先天免疫反应的最佳表达也至关重要。尽管广泛关注的是对IgE和特定抗原积极调节的元素（Ag）促炎性介质和MC的细胞因子的依赖性分泌，分子可以抑制此类反应的大小和/或持续时间的机制较少。我们最近报道说，Rabgefi（Rajb Guanine核丁基交换因子1）可能会对调节负调节。 RAS依赖性信号通路以及所有三类介体的分泌（预成型，脂质和细胞因子），在MCS中用IgE和特定Ag刺激。最近，我们发现Rabgefi也重要的是调节MC中的反应，这是由主要生存，发展和 MCS，SCF（干细胞因子，C-KIT配体）的增殖因子。值得注意的是，我们的Rabgefl^'鼠标展出与MC数量增加有关的皮肤的严重炎症，真皮MC的证据脱粒（即“激活”），以及血清中组胺和IgE的水平增加。中央我们现在希望解决的问题是：通过rabgefi的分子机制影响mc 开发，激活和功能，以及Rabgefi在MCS帐户中的这些行动在多大程度上可能对于Rabgefl^'小鼠中观察到的一些戏剧性表型异常？在目标1中。我们将调查 Rabgefi及其各个功能域如何负调节小鼠MC激活诱导通过在体外或体内通过FCERI或C-KIT（SCF受体）发出信号，并将识别和表征 Rabgefi相互作用的蛋白质及其在MC中的下游效应已通过这些激活接收者。在AIM 2中。我们将定义Rabgefi可以调节生存的机制， MC在体外和体内的发育，表型和增殖。体内研究将利用我们在缺乏或表达Rabgefi突变形式的WFRO衍生的MC中转移的能力 c-kit突变体，kitw/w〜v或套件“-3…”'*“通常MC缺陷小鼠（表达野生型Rabgefi）。我们因此，可以研究Rabgefi对只有MC缺乏或表达突变体形式的小鼠MC的影响，Rabgefi。阐明Rabgefi如何负面调节MC中的FCERI-或C-KIT依赖性信号传导将增加我们对MC激活和发展调节的理解，这是长期的这个项目的目标。这种工作也可能有助于开发新的治疗方法减轻疾病，例如哮喘和特应性皮炎，与IgE依赖性MC有关激活，在许多患者中，受影响组织中的MC数量增加。