Patterns of gene expression in Mulibrey Nanism

Mulibrey Nanism 中的基因表达模式

• 批准号: 6892111
• 负责人: JUAN M ZAPATA
• 金额: $ 9.55万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-05 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6892111
• 关键词: autosomal recessive trait; biological signal transduction; connective tissue growth factor; cytokine; developmental disease /disorder; developmental genetics; disease /disorder etiology; fibroblast growth factor; fibroblasts; gene expression; gene expression profiling; gene mutation; human tissue; mesoderm; microarray technology; nuclear factor kappa beta; polymerase chain reaction; protein sequence; protein structure function; protooncogene; tissue /cell culture; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): Mulibrey Nanism is an autosomal recessive growth disorder that affects several tissues of mesodermal origin. Severe growth failure of prenatal onset, constrictive pericardium with consequent hepatomegaly, hypoplasia of several endocrine glands with consequent hormonal deficiency, fibrosis of different organs, hydrocephaloid skull, and susceptibility to develop ovarian and Wilm's tumors characterize Mulibrey Nanism. A substantial portion of affected fetuses may be lost by early abortion, and infantile death is common. Mutations in the TRIM37 gene on chromosome 17q22-23 have been recently reported as the cause of this developmental syndrome. The investigator recently identified TRIM37 as a new TRAF domain encompassing protein. TRIM37 encodes a 964 amino acid residue protein and contains a tripartite domain (TRIM) in its N-terminus, an internal TRAF domain, and a polyacidic region with two nuclear localization signals at the C-terminus. Immunohistochemical analysis of human tissues indicates a tissue-restricted expression of TRIM37, and the analysis of its subcellular localization indicates that it can be found in cytosolic corpuscles and in nuclei, depending on the cell type. Preliminary studies on TRIM37 function indicate that it specifically interacts with Nmi and IFP35, two Myc- and STAT-binding proteins. Indeed FGF-dependent proliferative responses are compromised in Mulibrey Nanism cells, and over-expression of TRIM37 mutants inhibits c-Myc and NF-(B mediated transcription. Furthermore, a pilot analysis of the differences in gene expression profiles of skin fibroblasts from three different Mulibrey Nanism patients compared to those of normal fibroblasts indicate that Mulibrey Nanism cells express high levels of connective tissue growth factor (CTGF), a cytokine implicated in fibrogenesis. With this application, the investigators will seek to address the following questions about TRIM37: Specific Aim 1, what are the differences in gene expression profiles in normal donor cells and cells from Mulibrey Nanism patients? Specific Aim 2, is there any alteration in the patterns of gene expression induced by cytokines in normal and Mulibrey Nanism fibroblasts? Specific Aim 3, what is the role of TRIM37 in regulating gene expression?

描述（由申请人提供）：Mulibrey Nanism 是一种常染色体隐性生长障碍，影响多种中胚层来源的组织。 Mulibrey Nanism 的特点是产前严重生长障碍、心包收缩导致肝肿大、多个内分泌腺发育不全导致激素缺乏、不同器官纤维化、脑积水以及易患卵巢肿瘤和肾母细胞瘤。 很大一部分受影响的胎儿可能会因早期堕胎而流产，婴儿死亡也很常见。 最近报道称，染色体 17q22-23 上的 TRIM37 基因突变是导致这种发育综合征的原因。 研究人员最近发现 TRIM37 是一种新的 TRAF 结构域包含蛋白。 TRIM37 编码 964 个氨基酸残基的蛋白质，并在其 N 末端包含一个三联结构域 (TRIM)、一个内部 TRAF 结构域以及在 C 末端具有两个核定位信号的多酸区域。 人体组织的免疫组织化学分析表明 TRIM37 的组织限制性表达，其亚细胞定位分析表明，根据细胞类型，它可以在胞浆小体和细胞核中找到。 对 TRIM37 功能的初步研究表明，它与 Nmi 和 IFP35（两种 Myc 和 STAT 结合蛋白）特异性相互作用。事实上，FGF 依赖性增殖反应在 Mulibrey Nanism 细胞中受到损害，TRIM37 突变体的过度表达会抑制 c-Myc 和 NF-(B 介导的转录。此外，对来自三个不同 Mulibrey Nanism 患者的皮肤成纤维细胞与正常成纤维细胞的基因表达谱差异进行的初步分析表明，Mulibrey Nanism 细胞表达高水平的结缔组织生长因子 (CTGF)，这是一种与纤维发生有关的细胞因子。 通过该应用，研究人员将寻求解决有关 TRIM37 的以下问题： 具体目标 1，正常供体细胞和 Mulibrey Nanism 患者细胞的基因表达谱有何差异？ 具体目标 2，正常和 Mulibrey Nanism 成纤维细胞中细胞因子诱导的基因表达模式是否有任何改变？ 具体Aim 3、TRIM37在调控基因表达方面的作用是什么？