MOUSE MODELS TO STUDY MULIBREY NANISM

描述（由申请人提供）：本提案的目的是生成小鼠模型来研究多元纳米主义。据报道，染色体17q22-23上的Trim37基因在多发性Nanism患者中发生突变，多发性Nanism是一种常染色体隐性遗传病，影响几种中胚层起源的组织。多发性南氏症的特点是产前发病时严重的生长衰竭，几个内分泌腺体发育不全，导致激素缺乏，心包收缩，肝肿大，颅骨类脑积水，肌张力降低，易患卵巢和Wilm肿瘤。很大一部分受影响的胎儿可能因早期流产而丢失，婴儿死亡很常见。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发挥重要作用，但其作用的生化机制尚不清楚。Trim37编码一个964aa蛋白，在其n端包含一个三部分结构域（TRIM），一个内部TRAF结构域和一个具有两个核定位信号的多酸c端区域。初步的生物化学研究表明，该蛋白可能参与STAT和Myc通路的调控。利用本提案的资金，我们力求：产生缺乏TRIM37表达的小鼠谱系；2. 获得表达TRIM37 FINmajor突变的小鼠，该突变在多发性纳米症患者中发现；和3。研究trim37敲除和finmajor突变小鼠的发育和表型改变。这些小鼠将为进一步研究多发性骨髓瘤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.