Gene Responses in Basophil-Mediated Allergic Responses

嗜碱性粒细胞介导的过敏反应中的基因反应

• 批准号: 7988094
• 负责人: HUA HUANG
• 金额: $ 39万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7988094
• 关键词: Address; Allergens; Allergic; Allergic Disease; Anaphylaxis; Asthma; Atopic Dermatitis; Basophils; Chimera organism; Chromatin Structure; Country; Data; Defect; Development; Economic Burden; Gene Expression; Genes; Genetic Transcription; Hematopoietic System; Immune response; Incidence; Interleukin-3 Receptor; Interleukin-4; Interleukin-6; Knowledge; Luciferases; Mediating; Mediator of activation protein; Memory B-Lymphocyte; Messenger RNA; Methods; Modeling; Molecular; Phosphorylation; Play; Production; Reporter Genes; Rhinitis; Role; STAT5A gene; Series; Signal Transduction; Signaling Molecule; TSLP gene; Testing; Th2 Cells; United States; Work; allergic response; base; cost; in vivo; knock-down; mortality; novel; overexpression; promoter; public health relevance; receptor; research study; response; therapy development; transcription factor

DESCRIPTION (provided by applicant):The incidence and mortality of allergic diseases, such as anaphylaxis, allergic rhinitis, atopic dermatitis and asthma, have increased at an alarming rate in the Western countries in the past several decades. In the United States alone, over 50 million people suffer from allergic diseases. The economic burden of allergic diseases is staggering; it is estimated to cost $4 billion in 2006. Recent work has implied important roles for basophils in initiating, augmenting Th2-type immune responses to allergen challenges as well as maintaining B cell memory responses. Molecules, including IL-4, IL-6, and TSLP, have been demonstrated to be essential in mediating these novel basophil functions. However, due to the difficulty in obtaining sufficient numbers of basophils, how these key molecules are regulated at molecular levels is not understood. We have established an in vivo method to expand basophils rapidly and specifically. Based on our preliminary analyses, we hypothesize that STAT5 might form a transcription network with GATA2 and C/EBPa to regulate newly discovered basophil functions. We propose three aims to test our hypothesis. In Aim 1, we will analyze mechanisms by which C/EBPa regulates the Il4 gene. In Aim 2, we propose to determine how GATA2 regulate the Il4 gene in basophils. In Aim 3, we will determine how STAT5 forms a transcription network to regulate newly discovered basophil functions. Our proposal, if successfully accomplished, will significantly advance our understanding of how basophils mediate allergic immune responses at molecular levels. The knowledge gained will facilitate the development of treatments for allergic diseases and asthma. PUBLIC HEALTH RELEVANCE: This proposal aims to study how a regulatory network, consisting of STAT5, GATA2 and C/EBP1, regulates novel basophil functions during allergic immune responses.

说明（申请人提供）：过敏性疾病如过敏性反应、过敏性鼻炎、特应性皮炎和哮喘的发病率和死亡率在过去几十年中在西方国家以惊人的速度增长。仅在美国，就有超过5000万人患有过敏性疾病。过敏性疾病的经济负担是惊人的;据估计，2006年的费用为40亿美元。最近的研究表明，嗜碱性粒细胞在启动、增强Th 2型免疫应答以及维持B细胞记忆应答中具有重要作用。分子，包括IL-4，IL-6，和TSLP，已被证明是必不可少的，在介导这些新的嗜碱性粒细胞的功能。然而，由于难以获得足够数量的嗜碱性粒细胞，这些关键分子如何在分子水平上调节尚不清楚。我们已经建立了一种体内方法来快速和特异性地扩增嗜碱性粒细胞。基于我们的初步分析，我们推测STAT 5可能与GATA 2和C/EBPa形成一个转录网络来调节新发现的嗜碱性粒细胞功能。我们提出了三个目标来检验我们的假设。在目的1中，我们将分析C/EBPa调节IL 4基因的机制。在目的2中，我们提出确定GATA 2如何调节嗜碱性粒细胞中的IL 4基因。在目标3中，我们将确定STAT 5如何形成转录网络来调节新发现的嗜碱性粒细胞功能。我们的建议，如果成功实现，将显着推进我们的理解，嗜碱性粒细胞如何介导过敏性免疫反应在分子水平上。所获得的知识将促进过敏性疾病和哮喘治疗的发展。 公共卫生相关性：该提案旨在研究由STAT 5，GATA 2和C/EBP 1组成的调节网络如何在过敏性免疫应答期间调节新的嗜碱性粒细胞功能。