Function and regulation of GATA-3

描述(申请人提供)：T淋巴细胞(T细胞)不仅在针对各种病原体和恶性肿瘤的获得性免疫中发挥着非常重要的作用，而且在许多自身免疫性和过敏性疾病的发病机制中也起着重要的作用。GATA-3已成为控制T细胞发育和功能的关键转录因子。GATA-3不仅对T细胞谱系的发育至关重要，而且对产生包括IL-4、IL-5、IL-13和IL-10在内的T细胞细胞因子也很重要。此外，对过度表达GATA-3的基因工程小鼠的研究表明，GATA-3可能对T细胞生物学有更广泛的影响。因此，更好地了解GATA-3的功能和调控将极大地促进我们对免疫反应的启动、维持和停止的了解，并极大地提高我们操纵许多感染性、恶性、炎症性和自身免疫性疾病的结果的能力。然而，调控GATA-3表达的分子机制知之甚少，而且由于缺乏携带成熟蛋白的活体动物，对GATA-3功能的研究明显受阻 GATA-3缺陷的T细胞。这项资助申请旨在利用最近产生的条件性GATA-3缺陷小鼠来研究GATA-3在T细胞发育的后期阶段(目标1)以及在外周T细胞的不同亚群的功能中的调节作用和作用机制(目标2和3)。对于GATA-3在T细胞中的广泛功能，一个吸引人的解释是GATA-3能够与各种蛋白质在物理和功能上相互作用。这一可能性将通过几种体外方法解决(目标4)。此外，将致力于阐明介导GATA-3细胞类型特异性表达的分子机制(目标5)。

DESCRIPTION (provided by applicant): T lymphocytes (T cells) not only play very important roles in adaptive immunity against various pathogens and malignancies but also contribute substantially to the pathogenesis of many autoimmune and allergic diseases. GATA-3 has emerged as a key transcription factor that controls the development and function of T cells. GATA-3 is not only essential for the development of the T cell lineage but also important for the production of T cell cytokines, including IL-4, IL-5, IL-13, and IL-10. In addition, studies on genetically engineered mice over-expressing GATA-3 have implied that GATA-3 may have a broader effect on T cell biology. Therefore, a better understanding of the function and regulation of GATA-3 will significantly advance our knowledge about the initiation, maintenance, and cessation of immune responses, and greatly enhance our ability to manipulate the outcomes of many infectious, malignant, inflammatory, and autoimmune diseases. However, the molecular mechanisms regulating the expression of GATA-3 are poorly understood, and studies on the function of GATA-3 are markedly hampered by the lack of live animals carrying mature GATA-3-deficient T cells. This grant application is designed to take advantage of the recently generated conditional GATA-3-deficient mice to study the regulatory role and mechanism of action of GATA-3 in later stages of T cell development (Aim 1) and in the function of various subsets of peripheral T cells (Aims 2 and 3). One attractive explanation for the broad range of function of GATA-3 in T cells is that GATA-3 is able to interact physically and functionally with various proteins. This possibility will be addressed with several in vitro approaches (Aim 4). In addition, a great effort will be dedicated to elucidating the molecular mechanisms mediating the cell type-specific expression of GATA-3 (Aim 5).