权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
8233307
负责人：
Roberto Adachi
金额：
$ 41.29万
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/8233307
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. PUBLIC HEALTH RELEVANCE: Mast cells play important roles in inflammatory disorders and in the effective control of infections. We are creating mice with a selective deficiency in mast cell degranulation and we propose to test if they respond differently to models of allergic asthma, inflammatory arthritis and bacterial infections. We may identify a potential therapeutic target that could be either enhanced to increase our defenses against infectious organisms or suppressed to treat numerous inflammatory disorders.

描述(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。激活的肥大细胞会释放许多炎症介质。其中一些是预先形成的，储存在它们的分泌颗粒中，并通过脱颗粒释放出来，这是一种调节的胞吐作用。与其他肥大细胞反应不同，脱颗粒在炎症的发展和演变中的重要性尚不清楚。肥大细胞脱颗粒在早期过敏反应中起重要作用，因为组胺和5-羟色胺是通过这一机制分泌的。然而，我们最近发现，在脱颗粒过程中释放的肥大细胞类胰蛋白酶在炎症性关节炎和抵御细菌感染方面发挥着重要作用。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，Synaxins和Munc18蛋白是胞吐机制的重要组成部分。虽然Synaxins在胞吐作用中的确切作用已为人所知，但Munc18蛋白控制的胞吐步骤的特性仍然存在争议。Synaxins-3和-4以及Munc18-2和Munc18-3是肥大细胞表达的主要亚型。Munc18-3调节Synaxin-4，Munc18-2调节Synaxin-3。我们已经创造了肥大细胞中这四个基因中的每一个都有特定缺失的转基因小鼠。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的小鼠的单个肥大细胞，以揭示由每一种Synaxins介导的特定的胞外步骤，并由每一种Munc18蛋白调节。此外，我们将能够描述两个不同的Synaxin/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，我们将通过研究我们的肥大细胞脱颗粒缺陷小鼠在慢性过敏性哮喘、炎症性关节炎和细菌性肺炎模型中的作用，试图结束关于肥大细胞脱颗粒作用的范围和多样性的争论。我们的转基因小鼠可能会揭示肥大细胞脱颗粒是否是治疗某些炎症性疾病的有吸引力和安全的靶点。公共卫生相关性：肥大细胞在炎症性疾病和有效控制感染中发挥重要作用。我们正在创造肥大细胞脱颗粒存在选择性缺陷的小鼠，我们建议测试它们对过敏性哮喘、炎症性关节炎和细菌感染模型的反应是否不同。我们可以确定一个潜在的治疗靶点，既可以增强我们对感染性生物的防御，也可以抑制它来治疗大量的炎症性疾病。