Mechanism and pathophysiological significance of mast cell regulated exocytosis

肥大细胞调节胞吐作用的机制及病理生理学意义

基本信息

批准号：
8433311
负责人：
Roberto Adachi
金额：
$ 37.64万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
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：
2011-03-01 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8433311
关键词：
2,4-Dinitrophenol Abbreviations Adaptor Signaling Protein Affinity Alleles Allergic Allergic Reaction Allergic inflammation Animals Bacterial Infections Bacterial Pneumonia Biological Assay Bone Marrow Bovine Serum Albumin Bronchoalveolar Lavage Caenorhabditis elegans Calcium Carboxypeptidase Cell Degranulation Cell membrane Cell physiology Cells Cellular biology Chronic Chymase Clinical Colony-forming units Defect Development Disease Electric Capacitance Electron Microscopy Embryo Event Evolution Exocytosis Extrinsic asthma Failure Functional disorder Galactosidase Genes Genetic Recombination Histamine Human IgE IgE Receptors Immune Immune response Individual Infection Control Infectious Agent Inflammation Inflammation Mediators Inflammatory Interleukins Intervention Intravenous LacZ Genes Leukotrienes Mast Cell Stabilizer Mediating Modeling Morbidity - disease rate Mus Mutant Strains Mice N-ethylmaleimide-sensitive protein Neuroendocrine Cell Neurons Ovalbumin Participant Passive Cutaneous Anaphylaxis Play Process Property Prostaglandins Protein Isoforms Proteinase-Activated Receptors Proteins Proto-Oncogene Protein c-kit Reaction Relative (related person)Resistance Resolution Rheumatoid Arthritis Role S-nitro-N-acetylpenicillamine SNAP receptor Secretory Vesicles Serotonin Serum Albumin Site Staging Stem Cell Factor Synaptosomes TNF gene Testing Therapeutic Toxic effect Tryptase Tumor Necrosis Factor-alpha airway hyperresponsiveness allergic response anti-IgE cromoglycate cytokine embryonic stem cell human disease intraperitoneal lipid mediator mast cell public health relevance receptor recombinase research study respiratory response stem synaptotagmin syntaxin syntaxin 3 syntaxin 4 syntaxin binding protein 1 therapeutic target trafficking vesicle-associated membrane protein

项目摘要

DESCRIPTION (provided by applicant): Mast cells play important roles in inflammation and innate immune reactions. Activated mast cells release many inflammatory mediators. Some of them are preformed, stored in their secretory granules, and released via degranulation, a form of regulated exocytosis. The importance of degranulation, different to other mast cell responses, in the development and evolution of inflammation is not known. It is accepted that mast cell degranulation should be important in the early allergic response because histamine and serotonin are secreted through this mechanism. However, we have recently shown that mast cell tryptases released during degranulation play important roles in inflammatory arthritis and defense against bacterial infections. The effects of degranulation on the chronic stages of allergic and non-allergic inflammation are not known. Exocytosis is a highly regulated process, and Syntaxins and Munc18 proteins are essential components of the exocytic machinery. Although the precise role of Syntaxins in exocytosis is well known, the identity of the exocytic step controlled by Munc18 proteins remains controversial. Syntaxins-3 and -4, and Munc18-2 and -3 are the main isoforms expressed in mast cells. Munc18-3 regulates Syntaxin-4 and Munc18-2 regulates Syntaxin-3. We have created genetically-modified mice with specific deletions of each of these four genes in their mast cells. Preliminary studies in these mutant mice point to a severe and selective defect in mast cell regulated exocytosis. We plan to study single mast cells from these unique mice at high resolution to uncover the specific exocytic step mediated by each of these Syntaxins and regulated by each of these Munc18 proteins. Additionally, we will be able to describe how two different Syntaxin/Munc18 pairs control the same vesicular trafficking event. Then, moving from single cell to whole animal studies, we will try to end the controversy about the extent and versatility of the effects of mast cell degranulation by studying our mast cell degranulation- deficient mice in models of chronic allergic asthma, inflammatory arthritis, and bacterial pneumonia. Our genetically modified mice may reveal if mast cell degranulation is an attractive and safe therapeutic target for some inflammatory diseases.

描述（由申请人提供）：肥大细胞在炎症和先天免疫反应中发挥重要作用。激活的肥大细胞释放许多炎症介质。其中一些是预先形成的，储存在分泌颗粒中，并通过脱颗粒（一种受调节的胞吐作用的形式）释放。与其他肥大细胞反应不同，脱颗粒在炎症发生和演变中的重要性尚不清楚。人们普遍认为，肥大细胞脱颗粒在早期过敏反应中很重要，因为组胺和血清素是通过这种机制分泌的。然而，我们最近表明，脱粒过程中释放的肥大细胞类胰蛋白酶在炎症性关节炎和防御细菌感染中发挥重要作用。脱颗粒对过敏性和非过敏性炎症慢性阶段的影响尚不清楚。胞吐作用是一个高度调控的过程，突触蛋白和 Munc18 蛋白是胞吐机制的重要组成部分。尽管突触融合蛋白在胞吐作用中的确切作用众所周知，但由 Munc18 蛋白控制的胞吐步骤的身份仍然存在争议。 Syntaxins-3 和-4 以及Munc18-2 和-3 是肥大细胞中表达的主要亚型。 Munc18-3 调节 Syntaxin-4，Munc18-2 调节 Syntaxin-3。我们创造了转基因小鼠，其肥大细胞中这四个基因均被特定删除。对这些突变小鼠的初步研究表明，肥大细胞调节的胞吐作用存在严重的选择性缺陷。我们计划以高分辨率研究这些独特小鼠的单个肥大细胞，以揭示由每种突触融合蛋白介导并由每种 Munc18 蛋白调节的特定胞吐步骤。此外，我们将能够描述两个不同的 Syntaxin/Munc18 对如何控制相同的囊泡运输事件。然后，从单细胞研究转向整体动物研究，我们将通过在慢性过敏性哮喘、炎性关节炎和慢性过敏性哮喘模型中研究肥大细胞脱颗粒缺陷小鼠，试图结束关于肥大细胞脱颗粒影响的程度和多功能性的争论。细菌性肺炎。我们的转基因小鼠可能会揭示肥大细胞脱粒是否是某些炎症性疾病的有吸引力且安全的治疗靶点。