FUNCTION OF MAMMALIAN SINGLE MINDED GENES, SIM1 AND SIM2

哺乳动物单一基因 SIM1 和 SIM2 的功能

• 批准号: 2889387
• 负责人: CHEN-MING FAN
• 金额: $ 20.9万
• 依托单位: CARNEGIE INSTITUTION OF WASHINGTON, D.C.
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-01 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2889387
• 关键词: Downs syndrome; Drosophilidae; biochemical evolution; developmental genetics; developmental neurobiology; disease /disorder model; early embryonic stage; gene expression; gene targeting; genetic enhancer element; genetic mapping; genetic promoter element; genetically modified animals; histology; immunocytochemistry; in situ hybridization; laboratory mouse; nucleic acid sequence; phenotype; protein purification; tissue /cell culture

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.

描述（改编自研究者摘要）：本研究的目标 目的是研究哺乳动物Sim1和Sim2基因的功能 使用转基因小鼠模型。 Sim1和Sim2是 果蝇sim基因。 在飞行中，SIM扮演着重要的角色 在中枢神经系统的发展中起着重要作用。 的初步研究 小鼠Sim基因强烈提示进化上保守的功能。 SIM蛋白含有称为PAS结构域的保守序列基序， 它被几种环境传感器蛋白共享，例如二恶英 受体，缺氧诱导因子，果蝇昼夜节律 调节器Per和B。枯草芽孢杆菌芽孢形成调节因子KinA。 这 信息强烈表明，西姆斯也可以响应特定的 环境信号通过其PAS域。 该提案包括 以下目的：1）记录Sim1和Sim2在 2）建立缺乏Sim1和Sim2基因功能的小鼠模型， 同源重组和表征突变体表型， 评估这些基因的正常功能，以及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基因位于同线人类唐氏综合征关键基因中， 地区 此外，缺乏Sim1的突变小鼠表现出神经系统 可能与多发性硬化症有关的疾病。 探索和 鉴定调节Sim1和Sim2可能的小配体 功能将是开发方法以改变其功能的第一步。 体内基因活性。