SIM2 Regulation of Mitochondrial Dysfunction in Down Syndrome

总结 唐氏综合征（DS）是最常见的遗传性疾病，影响约1/750的新生儿， 美国每年。DS是由人类染色体长臂的全部或部分额外拷贝引起的 21（HSA 21）。DS表型是高度复杂和可变的，包括常见的表型， 特征性面部特征、智力残疾、骨骼肌无力和可变表型， 心脏缺陷、阿尔茨海默病、2型糖尿病和肥胖症的发病率增加。很明显， 线粒体功能障碍和氧化应激是DS相关病理的主要潜在因素。 在骨骼肌中，呼吸、ATP产生和线粒体结构的损伤已经被描述 以及DS患者和小鼠模型中的中枢神经系统。然而，驱动线粒体的机制 DS的功能障碍仍不清楚。我们已经证明，singleminded 2（SIM 2），一个最初被克隆的基因， HSA 21和bHLH/PAS蛋白家族的成员，在骨骼肌细胞中表达并调节 全系统代谢我们最近使用获得和丧失功能的细胞系和小鼠模型的结果表明， 发现SIM 2调节线粒体功能，不是作为经典的转录因子，而是通过直接相互作用 与线粒体和调节线粒体呼吸（MRC），可能通过相互作用， 线粒体呼吸链基于这些新的结果，我们假设Sim 2的表达增加， 在DS中，骨骼肌促进线粒体活性，导致氧化应激和线粒体 功能障碍为了解决这个问题，我们提出了三个具体目标。在目标1中，我们将确定 在DS的线粒体呼吸复合体中的SIM 2。我们还将定义物理基础， SIM 2和线粒体呼吸链复合体在代谢中的相互作用的结果。在Aim中 2，我们将确定Sim 2在DS相关的骨骼肌功能障碍中的作用，通过交叉井- 用Sim 2 +/-基因敲除小鼠建立DS小鼠模型Dp（16）1 Yey/+ DS。此外，我们将 还确定Sim 2的影响损失对线粒体周转和结构通过交叉mito-QC 用Sim 2 +/-小鼠的小鼠模型。在目标3中，我们将利用合成反义核酸的最新进展， 使用Sim 2阿索在细胞培养物和DS小鼠模型中开发和检测的寡核苷酸（阿索）技术 药物DS我们希望这些研究的结果将有助于确定线粒体功能障碍的机制 在DS。

SUMMARY Down Syndrome (DS) is the most common type of genetic disorder affecting approximately 1/750 newborns in the United States each year. DS is caused by an extra copy of all or part of the long arm of human chromosome 21 (HSA21). The DS phenotype is highly complex and variable including common phenotypes such characteristic facial features, intellectual disability, skeletal muscle weakness and variable phenotypes including heart defects, increased incidence of Alzheimer’s disease, type 2 diabetes and obesity. It is becoming clear that mitochondrial dysfunction and oxidative stress are major underlying factors in DS-related pathologies. Impairment in respiration, ATP production and mitochondria structure have been described in skeletal muscle and central nervous system in DS patients and mouse models. However, the mechanism driving mitochondrial dysfunction in DS is still not clear. We have shown that singleminded 2 (SIM2), a gene that was initially cloned on HSA21 and a member of the bHLH/PAS family of proteins, is expressed in skeletal muscle cells and regulates whole system metabolism. Our recent results using gain and loss function cell lines and mouse models have found that SIM2 regulates mitochondrial function, not as a classical transcription factor, but by interacting directly with mitochondria and modulating mitochondrial respiration (MRC), potentially through interaction with the mitochondria respiratory chain. Based on these new results, we hypothesize that increased expression of Sim2 in DS skeletal muscle promotes mitochondrial activity, resulting in increased oxidative stress and mitochondrial dysfunction. To address this hypothesis we propose three Specific Aims. In Aim 1, we will determine the role of SIM2 in the mitochondrial respiratory complex in DS. We will also define the physical basis for, and functional outcomes of, interactions between SIM2 and the mitochondria respiratory chain complex in metabolism. In Aim 2, we will determine the role of Sim2 in DS-associated skeletal muscle dysfunction by crossing the well- established DS mouse model, Dp(16)1Yey/+ DS, with whole body Sim2+/- knockout mice. In addition, we will also determine the impact loss of Sim2 has on mitochondrial turnover and structure by crossing the mito-QC mouse model with Sim2+/- mice. In Aim 3, we will take advantage of the recent advances in synthetic antisense oligonucleotide (ASO) technology to develop and test in cell culture and DS mouse models using a Sim2 ASO drug for DS. We expect results from these studies will help define the mechanism of mitochondrial dysfunction in DS.