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

基本信息

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
项目类别：
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&apos 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

项目摘要

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）是影响大约1/750新生儿的最常见遗传疾病类型每年美国。 DS是由全部或一部分人类染色体的额外副本引起的 21（HSA21）。 DS表型是高度复杂且可变的，包括常见的表型特征性的面部特征，智力残疾，骨骼肌无力和可变表型，包括心脏缺陷，阿尔茨海默氏病的增加，2型糖尿病和肥胖症。很明显线粒体功能障碍和氧化应激是与DS相关病理学的主要基础因素。在骨骼肌中描述了呼吸，ATP产生和线粒体结构的损害 DS患者和小鼠模型中的中枢神经系统。但是，驱动线粒体的机制 DS中的功能障碍尚不清楚。我们已经证明了Singlembines 2（Sim2），一个最初被克隆的基因在HSA21和BHLH/PAS蛋白家族的成员中，在骨骼肌细胞中表达并调节整个系统代谢。我们使用增益和损耗函数细胞系和鼠标模型的最新结果具有发现SIM2调节线粒体功能，而不是经典的转录因子，而是直接相互作用线粒体和调节线粒体呼吸（MRC），可能通过与线粒体呼吸链。基于这些新结果，我们假设增加了SIM2的表达在DS骨骼肌中，促进线粒体活性，导致氧化应激和线粒体增加功能障碍。为了解决这一假设，我们提出了三个具体目标。在AIM 1中，我们将确定角色 DS中线粒体呼吸复合物中的SIM2的of。我们还将定义物理基础和功能新陈代谢中SIM2和线粒体呼吸链复合物之间的相互作用的结果。目标 2，我们将通过跨越良好来确定SIM2在与DS相关的骨骼肌功能障碍中的作用已建立的DS鼠标模型DP（16）1yey/+ Ds，全身SIM2 +/-基因敲除小鼠。此外，我们将还可以通过穿越Mito-QC来确定SIM2对线粒体周转和结构的影响损失带有SIM2 +/-小鼠的鼠标模型。在AIM 3中，我们将利用合成反义的最新进展寡核苷酸（ASO）技术使用SIM2 ASO在细胞培养和DS小鼠模型中开发和测试 DS的药物。我们预计这些研究的结果将有助于定义线粒体功能障碍的机制在DS中。