IPSC phenotype, mitochondrial haplotype and psychosis in 22q11 deletion syndrome

22q11 缺失综合征中的 IPSC 表型、线粒体单倍型和精神病

基本信息

批准号：
9196885
负责人：
Stewart A Anderson
金额：
$ 58.58万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-20 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9196885
关键词：
22q11 22q11 Deletion Syndrome 22q11.2 Age Antioxidants Bioenergetics Bioinformatics Birth Child Chronic Complex Core Protein Cytochromes Data Development Disease Electron Transport Enrollment Functional disorder Future Genes Genetic Genus Hippocampus Goals Haplogroup Haplotypes International Investigation Lead Mediating Messenger RNA Metabolic Mitochondria Mitochondrial DNA Mitochondrial Proteins Morphology Mutation Neuronal Dysfunction Neurons Nuclear Oxidases Oxidative Phosphorylation Oxygen saturation measurement PTGS1 gene Patients Phenotype Prevention Process Prosencephalon Protein Biosynthesis Proteins Psychotic Disorders Reactive Oxygen Species Recording of previous events Ribosomes Risk Schizophrenia Secondary to Stem cells Symptoms System Technology Testing Therapeutic Agents Translating Translations Variant base brain behavior cohort computerized data processing conotruncal anomaly face syndrome cytochrome c oxidase gene function genetic analysis genetic risk factor genome editing genome sequencing high risk improved induced pluripotent stem cell mitochondrial dysfunction multidisciplinary neuropsychiatry novel novel strategies oxidative damage prospective protein expression protein function research study screening synaptogenesis whole genome

项目摘要

Metabolic compromise, including mitochondrial dysfunction, may contribute to the development of symptoms in schizophrenia. However, approaches to explore the relationship between mitochondrial dysfunction, neural dysfunction, and schizophrenia risk are needed. The most common genetic risk factor for schizophrenia is the 22q11.2 deletion syndrome (22q11DS), associated with a 25% risk of developing this disorder. Interestingly, in 22q11DS six of the roughly 40 deleted genes encode for mitochondrial-localizing proteins. We have assembled a multidisciplinary team to combine the use of stem cell derived neurons from 22q11DS patients with or without schizophrenia, and controls, with genetic analyses of 22q11DS patients with and without schizophrenia. We will test the hypothesis that a “second hit” within mitochondrial-related genes in the 22q11DS context increases metabolic dysfunction in neurons and is associated with an increased risk for schizophrenia in patients. Aim 1. Investigation of mitochondrial function in 22q11DS derived forebrain neurons. Existing IPSC lines from 3 groups will be compared: 1) 22q11DS with schizophrenia, 2) 22qDS without schizophrenia or history of psychosis (and over the age of 25), and healthy controls. Forebrain-like neurons from these lines will be compared for evidence of mitochondrial dysfunction that is most pronounced in the 22q11DS+SZ group. Consistent with the fact that one of the 22q11-deleted genes is MRPL40, a subunit of the mitochondrial ribosome, our preliminary evidence suggests that IPSC-derived neurons from the 22q11DS+SZ group have reduced translation of COX1, a key mitochondrial DNA-encoded protein. They also have significantly reduced cytochrome C oxidase activity, and strong evidence of oxidative damage. Aim 2. Are genetic “second hits” to mitochondrial function associated with psychosis in 22q11DS? We will use whole genome sequence data from about 600 22q11DS patients, evenly split between those with and without chronic psychosis, from the International 22q11.2DS Brain and Behavior Consortium (22QIBBC). Bioinformatic processing will determine whether the risk of developing SZ in 22q11DS is potentially influenced by the mitochondrial haplogroup, or is associated with an increased presence of mutations in mtDNA, or is associated with an increased presence of mutations in nuclear-encoded genes that generate mitochondrial- functioning proteins. Future studies would employ mitochondrial cybrids (`swapping”) technology, genome editing, “putback” experiments, and other approaches to test the functional relevance of findings from Aim 2 on mitochondrial function in 22q11DS-derived IPSCs, and could be extended to IPSCs from other high-risk SZ groups. These results could also be used to examine the prospective risk of 22q11DS children to develop chronic psychosis, using the large cohort of subjects currently being enrolled and studied by the 22QIBBC. Significance The results of this study could lead to improved prediction, treatment, and prevention of psychosis in 22q11DS, and could generalize to the treatment or prevention of psychosis beyond 22q11DS.

代谢受损，包括线粒体功能障碍，可能会导致症状的发生然而，探索线粒体功能障碍与神经之间关系的方法。精神分裂症最常见的遗传危险因素是。 22q11.2 缺失综合征 (22q11DS)，与 25% 的患此疾病的风险相关。 22q11DS 大约 40 个基因中的 6 个编码线粒体定位蛋白。多学科团队结合使用来自 22q11DS 患者的干细胞衍生神经元，有或没有我们对患有和不患有精神分裂症的 22q11DS 患者进行了遗传分析。将检验 22q11DS 环境中线粒体相关基因内的“第二次打击”增加的假设神经元代谢功能障碍，并与患者精神分裂症风险增加相关。目标 1. 研究 22q11DS 来源的前脑神经元的线粒体功能。将比较来自 3 组的现有 IPSC 系：1) 患有精神分裂症的 22q11DS，2) 不患有精神分裂症的 22qDS 精神分裂症或精神病史（25 岁以上），以及健康的前脑样神经元。将比较这些细胞系中线粒体功能障碍的证据，这种功能障碍在 22q11DS+SZ 组与 22q11 缺失基因之一是 MRPL40 的事实一致，MRPL40 是 MRPL40 的一个亚基。线粒体核糖体，我们的初步证据表明来自 22q11DS+SZ 的 IPSC 衍生神经元研究小组减少了 COX1 的翻译，COX1 是一种关键的线粒体 DNA 编码蛋白。细胞色素C氧化酶活性显着降低，氧化损伤的有力证据。目标 2. 线粒体功能的遗传“二次打击”是否与 22q11DS 中的精神病相关？我们将使用约 600 名 22q11DS 患者的全基因组序列数据，将这些患者平均分配且无慢性精神病，来自国际 22q11.2DS 大脑与行为联盟 (22QIBBC)。生物信息处理将确定 22q11DS 发生 SZ 的风险是否受到潜在影响由线粒体单倍群引起，或与 mtDNA 突变的增加有关，或与产生线粒体的核编码基因突变的增加有关未来的研究将采用线粒体细胞杂种（“交换”）技术、基因组。编辑、“回推”实验和其他方法来测试目标 2 的发现的功能相关性 22q11DS 衍生的 IPSC 中的线粒体功能，并且可以扩展到来自其他高风险 SZ 的 IPSC 这些结果还可用于检查 22q11DS 儿童发生的预期风险。慢性精神病，使用 22QIBBC 目前正在招募和研究的大量受试者。意义这项研究的结果可能会改善预测、治疗和预防 22q11DS 中的精神病，并且可以推广到 22q11DS 以外的精神病的治疗或预防。