Patterns of gene expression in Mulibrey Nanism

Mulibrey Nanism 中的基因表达模式

• 批准号: 6774628
• 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/6774628
• 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(申请人提供)：多布雷纳米症是一种常染色体隐性生长障碍，影响中胚层起源的几个组织。多器官发育迟缓、严重胎儿期发育迟缓、心包狭窄、肝脏肿大、多个内分泌腺发育不全、激素缺乏、不同器官纤维化、头颅积水、易发生卵巢肿瘤和肾母细胞瘤等。很大一部分受影响的胎儿可能会因早期流产而丢失，婴儿死亡是很常见的。最近有报道称，染色体17q22-23上的TRIM37基因突变是这种发育综合征的原因。这位研究人员最近确定TRIM37是一个新的TRAF结构域，包含蛋白质。TRIM37编码一个964个氨基酸残基的蛋白质，在其N端有一个三分结构域(TRIM)，在其内部有一个TRAF结构域，在C端有一个多酸区域，有两个核定位信号。对人类组织的免疫组织化学分析表明，TRIM37的表达具有组织限制性，对其亚细胞定位的分析表明，根据细胞类型的不同，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这两个Myc和STAT结合蛋白特异地相互作用。事实上，在Mulibrey Nanism细胞中，依赖于成纤维细胞生长因子的增殖反应受到损害，并且TRIM37突变体的过表达抑制了c-Myc和NF-(B)介导的转录。此外，初步分析了三种不同的多倍体纳米病患者皮肤成纤维细胞与正常成纤维细胞的基因表达谱差异，结果表明，多倍体纳米体细胞表达高水平的结缔组织生长因子(CTGF)，这是一种与纤维化形成有关的细胞因子。 通过这项应用，研究人员将试图解决以下关于TRIM37的问题：特定目标1，正常供体细胞和Mulibrey Nanism患者细胞的基因表达谱有什么差异？特定目的2，细胞因子诱导正常和多倍体纳米成纤维细胞的基因表达模式是否有改变？具体目标3，TRIM37在基因表达调控中的作用是什么？