MOUSE MODELS TO STUDY MULIBREY NANISM

描述（由申请人提供）： 该提案的目的是产生小鼠模型来研究Mulibrey Nanism。据报道，染色体17 q22 -23上的Trim 37基因在Mulibrey Nanism患者中发生突变，Mulibrey Nanism是一种影响中胚层起源的几种组织的常染色体隐性疾病。Mulibrey Nanism的特征是产前发作的严重生长障碍，几种内分泌腺发育不全，随之而来的激素缺乏，心包收缩，肝肿大，头状脑积水，肌肉张力减退和易患卵巢和Wilm肿瘤。很大一部分受影响的胎儿可能会失去早期流产和婴儿死亡是常见的。目前的治疗仅限于心包切除术和常规激素替代。因此，TRIM 37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仍然未知。Trim 37编码964个氨基酸的蛋白质，包括在其N-末端的三重结构域（TRIM）、内部TRAF结构域和具有两个核定位信号的多酸C-末端区域。对这种蛋白的生物化学的初步研究表明，它可能参与STAT和Myc通路的调节。在这项建议的资助下，我们希望：1。产生缺乏TRIM 37表达的小鼠谱系; 2.获得表达在Mulibrey侏儒症患者中发现的TRIM 37的FIN主要突变的小鼠;和3.研究trim 37基因敲除和FINmajor突变trim 37小鼠的发育和表型改变。这些小鼠将成为进一步研究Mulibrey Nanism生物学和病因学的基础。

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.