SIM2 Regulation of Mitochondrial Dysfunction in Down Syndrome

SIM2 对唐氏综合症线粒体功能障碍的调节

• 批准号: 10654384
• 负责人: Weston W Porter
• 金额: $ 196.02万
• 依托单位: TEXAS A&M AGRILIFE RESEARCH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-13 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10654384
• 关键词: Address; Aerobic; Affect; Alzheimer' s Disease; Antisense Oligonucleotides; Automobile Driving; Biogenesis; Brain; Breast; Cell Culture Techniques; Cell Line; Central Nervous System; Characteristics; Chromosome 21; Circulation; Clinical Trials; Complex; Data; Development; Disease; Down Syndrome; Energy Metabolism; Etiology; Eukaryotic Cell; Face; Functional disorder; Gene Expression; Genes; Genetic Diseases; Glycolysis; Health; Heart; Heart Abnormalities; Human; Human Chromosomes; Impairment; Incidence; Intellectual functioning disability; Kidney; Knockout Mice; Metabolic Diseases; Metabolic Pathway; Metabolism; Mind; Mitochondria; Mitochondrial DNA; Multienzyme Complexes; Mus; Muscle Fibers; Muscle function; Mutation; Newborn Infant; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oxidative Stress; Palate; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Physiological; Play; Production; Protein Family; Proteins; Regulation; Respiration; Respiratory Chain; Role; Skeletal Muscle; Structure; Subcutaneous Injections; System; Technology; Testing; Tissues; United States; Up-Regulation; arm; effective therapy; functional outcomes; gain of function; induced pluripotent stem cell; intravenous injection; loss of function; member; mitochondrial dysfunction; mouse model; new therapeutic target; overexpression; respiratory; skeletal muscle weakness; spine bone structure; therapeutic target; transcription factor

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.

概括 唐氏综合症 (DS) 是最常见的遗传性疾病类型，影响大约 1/750 的新生儿 每年美国。 DS 是由人类染色体全部或部分长臂的额外拷贝引起的 21（HSA21）。 DS 表型高度复杂且多变，包括常见表型，例如 特征性面部特征、智力障碍、骨骼肌无力和可变表型，包括 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。越来越清楚的是 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。 骨骼肌中的呼吸、ATP 生成和线粒体结构受损已被描述 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。我们已经证明了最初克隆的单一思维 2 (SIM2) 基因 HSA21 和 bHLH/PAS 蛋白家族的成员，在骨骼肌细胞中表达并调节 整个系统的新陈代谢。我们最近使用增益和损失函数细胞系和小鼠模型的结果表明 发现 SIM2 不是作为经典转录因子，而是通过直接相互作用来调节线粒体功能 与线粒体并调节线粒体呼吸（MRC），可能是通过与 线粒体呼吸链。基于这些新结果，我们假设 Sim2 的表达增加 DS 骨骼肌中的 促进线粒体活性，导致氧化应激增加和线粒体 功能障碍。为了解决这个假设，我们提出了三个具体目标。在目标 1 中，我们将确定角色 DS 中线粒体呼吸复合体中 SIM2 的存在。我们还将定义物理基础和功能 SIM2 与代谢中线粒体呼吸链复合体之间相互作用的结果。瞄准 2、我们将通过交叉实验来确定 Sim2 在 DS 相关骨骼肌功能障碍中的作用 建立DS小鼠模型，Dp(16)1Yey/+ DS，全身Sim2+/-基因敲除小鼠。此外，我们将 还通过穿过 mito-QC 确定 Sim2 损失对线粒体周转和结构的影响 使用 Sim2+/- 小鼠的小鼠模型。在目标 3 中，我们将利用合成反义的最新进展 使用 Sim2 ASO 在细胞培养和 DS 小鼠模型中开发和测试寡核苷酸 (ASO) 技术 DS药物。我们期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 中。