Immunobiology of MINA53

MINA53 的免疫生物学

• 批准号: 7712947
• 负责人: Mark Bix
• 金额: $ 29.4万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-23 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7712947
• 关键词: Affect; Alleles; Allergens; Allergic; Asthma; Autoimmune Diseases; Binding; Biological Assay; Blood; CD4 Positive T Lymphocytes; Case-Control Studies; Cells; Child; Clinic; Crows; Data; Development; Diagnostic; Disease; Disease Association; EMSA; Enrollment; Etiology; Evaluation; Family member; Frequencies; General Population; Genes; Genetic Markers; Genetic Transcription; Government; Helper-Inducer T-Lymphocyte; Hereditary Disease; Histones; Human; Human Genetics; IL4 gene; Immune response; Immunobiology; Individual; Interleukin 4 Receptor; Interleukin-13; Life; Linkage Disequilibrium; Mainstreaming; Methods; Molecular Genetics; Mono-S; Mus; Mutation; Nuclear Antigens; Persons; Protein Family; Reporter; Research Personnel; Risk; Risk Factors; Role; Sum; T-Lymphocyte; Testing; Therapeutic Intervention; Tolerogen; Transgenic Animals; Variant; Yin; base; chromatin immunoprecipitation; cohort; disorder risk; genetic association; genetic regulatory protein; healthy volunteer; human disease; novel; pathogen; public health relevance

DESCRIPTION (provided by applicant): In humans, IL4 and TH2 cells critically impact a wide array of diseases, a prime example of which is bronchial asthma where genetic association studies have repeatedly identified both the gene locus encoding IL4 and IL13 (5q25-31) and several mutations in the IL4 receptor alpha chain as strong disease risk factors REF. We recently identified Mina53 as a gene in mice encoding an IL4 regulatory protein that cell autonomously regulates TH2 bias, the propensity of naive CD4 cells to develop into IL4 secreting TH2 cells [1]. Mina53, first identified as a Myc-induced nuclear antigen of 53kd [2], belongs to the Jmj protein family whose hallmark JmjC domain was shown recently in multiple family members to possess histone demethylase activity [3-9]. Murine Mina53 is induced rapidly in naive T helper cells to levels that are inversely correlated with those of IL4, being high in low-TH2 biased strains and low in high-TH2 biased strains, suggesting an IL4/TH2 inhibitory role. Consistent with this, EMSA, chromatin immunoprecipitation (ChIP), transient reporter and transgenic animal assays demonstrate that Mina53 specifically binds to and represses transcription from the IL4 gene. Together, these data support the central hypothesis of this proposal that in human T cells, MINA53 represses IL4 expression, thereby critically influencing TH2 development and TH2-dependent disease. We will test this hypothesis by determining: (1) the role of MINA53 in regulating IL4 and TH2 bias in human T helper cells; and (2) whether variation in the MINA53 locus associates with the TH2-dependent disease bronchial asthma. The long-term objective of this proposal is to understand the molecular and genetic basis for IL4/TH2- dependent disease and to identify novel targets for diagnostic and therapeutic intervention. PUBLIC HEALTH RELEVANCE: The global significance of this proposal arises from the critical role of TH2 bias in immune responses elicited by tolerogens, pathogens and allergens. Deeper mechanistic understanding of TH2 bias and its role in bronchial asthma may provide new targets for diagnostic and therapeutic interventions for asthma as well as for other TH2-dependent disease of autoimmune, infectious and allergic etiology affecting the lives of millions of people.

描述（申请人提供）：在人类中，IL 4和TH 2细胞严重影响多种疾病，其中一个最好的例子是支气管哮喘，其中遗传关联研究反复鉴定了编码IL 4和IL 13的基因位点（5 q25 -31）和IL 4受体α链中的几个突变作为强烈的疾病风险因素REF。我们最近在小鼠中鉴定了Mina 53作为编码IL 4调节因子的基因。细胞自主调节TH 2偏好的蛋白质，幼稚CD 4细胞发育成分泌IL 4的TH 2细胞的倾向[1]。Mina 53首先被鉴定为Myc诱导的53 kd的核抗原[2]，属于Jmj蛋白家族，其标志性JmjC结构域最近在多个家族成员中显示具有组蛋白脱甲基酶活性[3-9]。小鼠Mina 53在初始T辅助细胞中被快速诱导至与IL 4的水平负相关的水平，在低TH 2偏向的菌株中高而在高TH 2偏向的菌株中低，表明IL 4/TH 2抑制作用。与此一致，EMSA、染色质免疫沉淀（ChIP）、瞬时报告基因和转基因动物测定证明Mina 53特异性结合IL 4基因并抑制IL 4基因的转录。总之，这些数据支持了该提议的中心假设，即在人T细胞中，MINA 53抑制IL 4表达，从而严重影响TH 2发育和TH 2依赖性疾病。我们将通过以下方法来检验这一假设：（1）MINA 53在调节人辅助性T细胞中IL 4和TH 2偏好中的作用;（2）MINA 53基因座的变异是否与TH 2依赖性支气管哮喘相关。该提案的长期目标是了解IL 4/TH 2依赖性疾病的分子和遗传基础，并确定诊断和治疗干预的新靶点。公共卫生关系：这一提议的全球意义源于TH 2偏好在耐受原、病原体和过敏原引起的免疫应答中的关键作用。对TH 2偏倚及其在支气管哮喘中的作用的更深入的机制理解可能为哮喘以及影响数百万人生活的其他自身免疫性、感染性和过敏性病因的TH 2依赖性疾病的诊断和治疗干预提供新的靶点。