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

基本信息

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
项目类别：
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

项目摘要

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进展导致了几种拷贝数变体的识别（CNV）和与精神分裂症极高的风险相关的单基因。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独立起作用还是破坏一组共同集合产生类似临床表型的神经生物学途径。研究3q29缺失的影响， CNV赋予精神分裂症的风险增加40倍，这表明线粒体功能可能会受到破坏在发展中心神经系统中。令人惊讶的是，具有精神分裂症风险最强的CNV （22q11.2del）也据报道产生线粒体表型。除了3Q29和22Q11.2 删除，至少九个其他神经发育障碍相关的CNV基因座也包含编码的基因线粒体蛋白。这些数据激发了神经线粒体可能是收敛部位的假设精神分裂风险CNV下游的生物学。这个职业发展项目旨在解决这个问题假设通过线粒体神经生物学进行了广泛的新培训。我已经开发了一组独特的等源性人类诱导的多能干细胞系，结合每个CNV的小鼠实验模型，将利用3q29和22q11.2删除类似地破坏线粒体功能的假设在发展中的神经系统中。该项目的目标是确定这些项目产生的线粒体表型的程度精神分裂症相关的CNV，并确定分子和功能水平。为此，我们将评估每个CNV对分离线粒体蛋白质组的影响来自CNV模型小鼠脑和等源性人皮质器官。另外，从糖酵解的过渡氧化磷酸化是神经元发育的关键阶段。我们将测试3q29删除的容量和22q11.2缺失神经祖细胞通过使用培养基制剂来适应代谢应激利用糖酵解或氧化磷酸化来满足能量需求的培养物。最后，我们将使用一种设计的异源细胞系统，用于筛选3Q29线粒体表型的基因驱动因素。这些实验将产生与融合生物学概念有关的重要数据，这是及时且重要的转化精神病学的问题可能会对我们对风险等位基因和风险等位基因的理解产生深远影响未来的治疗方法。