Phenotypic convergence at mitochondria in copy number variant disorders

拷贝数变异性疾病中线粒体的表型趋同

• 批准号: 10723885
• 负责人: Ryan Herndon Purcell
• 金额: $ 14.34万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10723885
• 关键词: 22q11; 22q11.2; 3q29; Address; Alleles; Astrocytes; Biological; Biological Assay; Biological Models; Biology; Brain; Cell Line; Cell Respiration; Cells; Central Nervous System; Complex; Copy Number Polymorphism; Data; Disease; Engineering; Experimental Models; Female; Flow Cytometry; Formulation; Foundations; Future; Galactose; Genes; Genetic; Genus Hippocampus; Glycolysis; Goals; Human; Human Cell Line; Immunofluorescence Immunologic; Impairment; Lentivirus; Link; Measures; Mentors; Metabolic; Metabolic stress; Mitochondria; Mitochondrial Proteins; Modeling; Molecular; Mus; National Institute of Mental Health; Neocortex; Nervous System; Neurobiology; Neurodevelopmental Disorder; Neurons; Organoids; Oxidative Phosphorylation; Oxygen Consumption; Pathway interactions; Perinatal; Phenotype; Pluripotent Stem Cells; Postdoctoral Fellow; Process; Proteins; Proteome; Proteomics; Psychiatry; Reporting; Research; Research Support; Respiration; Ribosomes; Same-sex; Schizophrenia; Site; Stress; System; Testing; Therapeutic; Tissues; Titrations; Training; Validation; Work; biomarker panel; career development; clinical phenotype; cohort; comparison control; design; differential expression; disorder risk; experience; experimental study; genomic locus; high risk; induced pluripotent stem cell; knock-down; male; mouse model; neonatal mice; nerve stem cell; neural; neurogenesis; neuron development; neuropsychiatry; postnatal; premature; programs; psychiatric genomics; psychogenetics; risk variant; schizophrenia risk; screening; single-cell RNA sequencing; skills; stem; stoichiometry; tool; transcriptomics

PROJECT SUMMARY/ABSTRACT Substantial progress in psychiatric genomics has led to the identification of several copy number variants (CNVs) and single genes that are associated with extremely high risk for schizophrenia. A major question facing the field now is whether these discrete genomic loci all act independently or disrupt a common set of neurobiological pathways to produce a similar clinical phenotype. Studies on the effects of the 3q29 deletion, a CNV that confers >40-fold increased risk for schizophrenia, indicate that mitochondrial function may be disrupted in the developing central nervous system. Strikingly, the CNV with the next strongest risk for schizophrenia (22q11.2Del) has also been reported to produce mitochondrial phenotypes. In addition to the 3q29 and 22q11.2 deletion, at least nine other neurodevelopmental disorder-associated CNV loci also contain genes that encode mitochondrial proteins. These data motivate the hypothesis that neural mitochondria may be a site of convergent biology downstream of schizophrenia-risk CNVs. This career development project is designed to address this hypothesis with extensive new training in mitochondrial neurobiology. I have developed a unique set of isogenic human induced pluripotent stem cell lines that, in combination with mouse experimental models of each CNV, will be leveraged to test the hypothesis that 3q29 and 22q11.2 deletion similarly disrupt mitochondrial function in the developing nervous system. The goals of this project are to define the extent of mitochondrial phenotypes produced by these schizophrenia-associated CNVs and to determine the degree of biological convergence at molecular and functional levels. To this end we will assess the effects of each CNV on the proteome of mitochondria isolated from CNV-model mouse brain and isogenic human cortical organoids. Additionally, the transition from glycolysis to oxidative phosphorylation is a critical stage of neuronal development. We will test the capacity of 3q29 deletion and 22q11.2 deletion neural progenitor cells to adapt to metabolic stress by using media formulations to force cultures to either utilize glycolysis or oxidative phosphorylation to meet energy demands. Finally, we will utilize an engineered heterologous cell system to screen for gene drivers of 3q29 mitochondrial phenotypes. These experiments will yield important data related to the concept of convergent biology, a timely and significant question in translational psychiatry which could have profound effects on our understanding of risk alleles and future therapeutic approaches.

项目摘要/摘要 精神病基因组学的实质性进展导致了几个拷贝数变异的鉴定 （CNVs）和与精神分裂症极高风险相关的单个基因。面临的主要问题 现在的领域是这些离散的基因组基因座是否都独立作用或破坏一组共同的基因组 神经生物学途径来产生相似的临床表型。3q 29基因缺失的研究 CNV使精神分裂症的风险增加>40倍，表明线粒体功能可能被破坏 中枢神经系统的发育。令人惊讶的是，CNV与精神分裂症的下一个最大风险 （22q11.2Del）也被报道产生线粒体表型。除了3q 29和22q11.2 除CNV基因缺失外，至少9个其他神经发育障碍相关的CNV基因座也含有编码 线粒体蛋白这些数据激发了这样的假设，即神经线粒体可能是会聚的位点。 精神分裂症风险CNVs的下游生物学。这个职业发展项目旨在解决这一问题 在线粒体神经生物学方面接受了广泛的新培训。我开发了一套独特的同基因 人诱导多能干细胞系，与每种CNV的小鼠实验模型组合， 将被用来检验3q 29和22q11.2缺失类似地破坏线粒体功能的假设 在发育中的神经系统。 该项目的目标是确定由这些细胞产生的线粒体表型的程度。 精神分裂症相关CNVs并确定分子和生物学收敛程度 功能层次。为此，我们将评估每种CNV对分离的线粒体蛋白质组的影响。 来自CNV模型小鼠脑和同基因人类皮质类器官。此外，糖酵解的转变 氧化磷酸化是神经元发育的关键阶段。我们将测试3q 29缺失的能力 和22q11.2缺失神经祖细胞以适应代谢应激， 利用糖酵解或氧化磷酸化来满足能量需求。最后，我们将利用 一种工程化异源细胞系统，用于筛选3q 29线粒体表型的基因驱动。这些 实验将产生与收敛生物学概念相关的重要数据，这是一个及时而重要的 翻译精神病学中的一个问题，这可能对我们对风险等位基因的理解产生深远的影响， 未来的治疗方法。