A Mouse Model for Schimke Immuno-osseous Dysplasia

描述（由申请人提供）： Schimke免疫性骨发育不良（SIOD）是一种常染色体隐性遗传的致死性多系统疾病。SIOD的特征包括骨骼发育不良、肾功能衰竭和T细胞缺乏等不变的发现，以及其他症状，如软骨发育不良、动脉硬化和甲状腺功能减退。SIOD是由SMARCAL 1（swi/snf相关的、基质相关的、染色质的肌动蛋白依赖性调节子、亚家族a样1）中的功能缺失突变引起的，SMARCAL 1编码与SF 2解旋酶和SNF 2染色质重塑蛋白具有同源性的蛋白质。SMARCAL 1存在于细胞核和细胞质中。在Hela细胞的细胞核内，SMARCAL 1形成聚集体，其经常与卷曲蛋白（Cajal小体的标记物）共定位，并且当在果蝇中表达时，其特异性地结合常染色质DNA。我们的果蝇遗传学研究表明，SMARCAL 1是Polycomb组蛋白的拮抗剂，在三胸蛋白BRM的上游发挥作用。我们的观察表明SMARCAL 1可能作为SNF 2相关的染色质重塑蛋白或DNA解旋酶调节RNA转录或加工。为了将我们的生化、细胞系和果蝇研究的结果扩展到理解SIOD的病理生理学，需要哺乳动物模型。因此，本申请的目的是通过表征野生型骨发育的Smarcal 1表达、骨发育中Smarcal 1的过表达和骨发育中Smarcal 1表达的缺失来表征SMARCAL在骨骼发育和维持中的作用。最终，我们的目标是了解Smarcal 1在哺乳动物生物学中的作用，阐明SIOD背后的人类生物学，并利用这种理解来改善或治疗SIOD和相关疾病。R21提供的资金对我来说至关重要，作为一名新的研究人员，开发这些小鼠模型。

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.