A Mouse Model for Schimke Immuno-osseous Dysplasia

描述(申请人提供)：Schimke免疫性骨发育不良(SIOD)是一种常染色体隐性遗传性致死性多系统疾病。SIOD的特征包括骨骼发育不良、肾功能衰竭和T细胞缺陷等不变的表现，以及其他症状，如肥胖、动脉硬化和甲状腺功能减退。SIOD是由SMARCAL1(SWI/SNF相关，基质相关，染色质肌动蛋白依赖性调节蛋白，α-样亚家族)功能缺失突变引起的，SMARCAL1编码的蛋白与SF2解旋酶和SNF2染色质重塑蛋白同源。SMARCAL1存在于胞核和胞浆中。在Hela细胞的细胞核内，SMARCAL1形成聚集体，经常与Cajal小体的标记物Colin共定位，当在果蝇中表达时，它特异性地结合常染DNA。我们的果蝇遗传学研究表明，SMARCAL1是Polycomb组蛋白的拮抗剂，功能位于三胸蛋白BRM的上游。我们的观察表明，SMARCAL1可能作为SNF2相关的染色质重塑蛋白或DNA解旋酶来调节RNA的转录或加工。为了将我们的生化、细胞系和果蝇研究结果扩展到理解SIOD的病理生理学，需要一个哺乳动物模型。因此，本应用的目的是通过鉴定Smarcal1在野生型骨发育中的表达、Smarcal1在骨发育中的过度表达以及Smarcal1在骨发育中的缺失来表征SMARCAL在骨骼发育和维持中的作用。最终，我们的目标是了解Smarcal1在哺乳动物生物学中的作用，阐明SIOD背后的人类生物学，并利用这一理解来改善或治疗SIOD和相关疾病。作为一名新的研究人员，R21提供的资金对我开发这些小鼠模型至关重要。

DESCRIPTION (provided by applicant): Schimke immuno-osseous dysplasia (SIOD) is an autosomal recessive fatal multisystem disease. The features of SIOD include the invariant findings of skeletal dysplasia, renal failure, and T cell deficiency as well as other symptoms such as adontia, arteriosclerosis, and hypothyroidism. SIOD is caused by loss-of-function mutations in SMARCAL1 (swi/snf related, matrix associated, actin dependent regulator of chromatin, subfamily a-like 1), which encodes a protein with homology to SF2 helicases and SNF2 chromatin remodeling proteins. SMARCAL1 resides in both the nucleus and the cytoplasm. Within the nucleus of Hela cells, SMARCAL1 forms aggregates that frequently co-localize with coilin, a marker of Cajal bodies, and when expressed in Drosophila, it specifically binds euchromatic DNA. Our Drosophila genetic studies have shown that SMARCAL1 is an antagonist of Polycomb group proteins and functions upstream of the trithorax protein BRM. Our observations suggest that SMARCAL1 potentially regulates RNA transcription or processing as a SNF2-related chromatin remodeling protein or as a DNA helicase. To extend the results from our biochemical, cell line, and Drosophila studies to understanding the pathophysiology of SIOD requires a mammalian model. Therefore the objective of this application is to characterize the role of SMARCAL in skeletal development and maintenance through characterization of Smarcal1 expression for wild-type bone development, over-expression of Smarcal1 in bone development, and loss of Smarcal1 expression in bone development. Ultimately our goal is to understand the role of Smarcal1 in mammalian biology, to clarify the human biology underlying SIOD and to use this understanding to ameliorate or treat SIOD and related diseases. The funding provided by this R21 is critical for me, as a new investigator, to develop these murine models.