FUNCTION OF MAMMALIAN SINGLE MINDED GENES, SIM1 AND SIM2

描述（改编自研究者的摘要）：本研究的目标 提案是研究哺乳动物 Sim1 和 Sim2 基因的功能 使用转基因小鼠模型。 Sim1 和 Sim2 是 果蝇 sim（一心一意）基因。 在飞行过程中，SIM 发挥着重要作用 在中枢神经系统的发育中。 初步研究 小鼠 Sim 基因强烈表明其功能在进化上是保守的。 SIM 蛋白含有称为 PAS 结构域的保守序列基序， 多种环境传感器蛋白（例如二恶英）所共享 受体，缺氧诱导因子，果蝇昼夜节律 调节器 Per 和枯草芽孢杆菌孢子形成调节器 KinA。 这个 信息强烈表明 SIM 也可能对特定的 通过其 PAS 域发出环境信号。 该提案包括 以下目标：1）记录 Sim1 和 Sim2 的表达模式 细节； 2) 建立Sim1和Sim2基因功能缺失小鼠模型 同源重组和表征突变表型，以便 评估这些基因的正常功能，3) 识别可能的小基因 调节 Sim1 和 Sim2 功能的分子配体。 重要的是， 小鼠Sim2基因位于同线性人类唐氏综合症关键 地区。 此外，缺乏 Sim1 的突变小鼠表现出神经功能 可能与多发性硬化症有关的疾病。 探索与 鉴定可能调节 Sim1 和 Sim2 的小配体 功能将是开发改变其功能的方法的第一步 体内基因活性。

DESCRIPTION (adapted from investigator's abstract): The goal of this proposal is to investigate the function of mammalian Sim1 and Sim2 genes using transgenic mouse models. Sim1 and Sim2 are homologues of the Drosophila sim (singleminded) gene. In the fly, sim plays essential roles in the development of the central nervous system. Preliminary studies of the mouse Sim genes strongly suggest evolutionarily conserved functions. The SIM proteins contain conserved sequence motif termed the PAS domain, which is hared by several environmental sensor proteins such as the Dioxin receptor, the Hypoxia Inducible Factor, the Drosophila circadian rhythm regulator Per, and the B. subtilis sporulation regulator KinA. This information strongly indicated that SIMs may also respond to specific environmental signals via their PAS domains. This proposal includes the following aims: 1) documenting the expression patterns of Sim1 and Sim2 in detail; 2) establishing mouse models lacking Sim1 and Sim2 gene function by homologous recombination and characterizing mutant phenotypes in order to assess the normal function of these genes, and 3) identifying possible small molecule ligands that modulate the function of Sim1 and Sim2. Importantly, the mouse Sim2 gene is located in the syntenic human Down syndrome critical region. Furthermore, mutant mice lacking Sim1 display neurological disorders that may relate to multiple sclerosis. Exploration and identification of possible small ligands that regulate Sim1 and Sim2 function will be the first step towards developing methods to alter their gene activities in vivo.