MOUSE MODELS TO STUDY MULIBREY NANISM

描述(由申请者提供)：本提案的目的是建立研究Mulibrey Nanism的小鼠模型。据报道，染色体17q22-23上的Trim37基因在多发性纳米症患者中发生突变，这是一种常染色体隐性遗传病，影响中胚层起源的几个组织。多发性纳米症的特点是出生前严重的生长障碍，几个内分泌腺发育不良继而导致激素缺乏，心包狭窄，肝肿大，脑积水，肌肉低张力，易发生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流产而丢失，婴儿死亡是很常见的。目前的治疗仅限于心包切除术和常规激素替代。因此，TRIM37在人类发育和肿瘤发生中起着重要作用，但该蛋白的生化作用机制尚不清楚。Trim37编码一个964氨基酸的蛋白质，其N-端包含一个三分结构域(TRIM)、一个内部TRAF结构域和一个带有两个核定位信号的多酸性C-末端区域。对该蛋白生物化学的初步研究表明，它可能参与了STAT和Myc通路的调节。在这项计划的资助下，我们寻求：1.建立一个缺乏TRIM37表达的小鼠谱系；2.获得表达在Mulibrey Nanism患者中发现的TRIM37的FIN主要突变的小鼠；以及3.研究Trim37基因敲除和FIN主要突变的Trim37小鼠的发育和表型变化。这些小鼠将为进一步研究Mulibrey Nanism的生物学和病因学奠定基础。

DESCRIPTION (provided by applicant): The aim of this proposal is the generation of mouse models to study Mulibrey Nanism. The Trim37 gene on chromosome 17q22-23 was reported to be mutated in patients with Mulibrey Nanism, an autosomal recessive disorder that affects several tissues of mesodermal origin. Mulibrey Nanism is characterized by severe growth failure of prenatal onset, hypoplasia of several endocrine glands with consequent hormonal deficiency, constrictive pericardium, hepatomegaly, hydrocephaloid skull, muscle hypotonia and susceptibility to develop ovarian and Wilm's tumors. A substantial portion of affected fetuses may be lost by early abortion and infantile death is common. Current treatment is limited to pericardiectomy and routine hormone replacement. Thus, TRIM37 plays important roles in human development and tumorigenesis, but the biochemical mechanism of action of the protein remains unknown. Trim37 encodes a 964 aa protein encompassing a tripartite domain (TRIM) in its N-terminus, an internal TRAF domain, and a polyacidic C-terminal region with two nuclear localization signals. Preliminary studies of the biochemistry of this protein suggest that it might be involved in the regulation of STAT and Myc pathways. With funding of this proposal, we seek to: 1. generate a mouse lineage lacking TRIM37 expression; 2. obtain mice expressing the FINmajor mutation of TRIM37 found in patients with Mulibrey Nanism; and 3. study the developmental and phenotypic alterations of trim37 knock out and FINmajor-mutated trim37 mice. These mice will be the foundation for further studies on the biology and etiology of Mulibrey Nanism.