Molecular and Cellular Mechanisms of Chromosome 18q23 Dysmyelination

染色体 18q23 髓鞘脱失的分子和细胞机制

基本信息

批准号：
10592982
负责人：
JANNINE De Mars CODY
金额：
$ 11.63万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
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：
2023-06-23 至 2025-05-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10592982
关键词：
18q Acceleration Address Age-associated memory impairment Attentional deficit Basic Science Brain Cell Line Cell model Cell physiology Cells Cellular Neurobiology Characteristics Chromosome 18 Chromosome Deletion Chromosomes Clinical Clinical Investigator Clinical Research Collaborations Conduct Clinical Trials Cultured Cells DNA Data Defect Development Developmental Process Dose Drug Screening Drug toxicity Drug usage Effectiveness Evaluation Failure Fibroblasts Future Genes Genetic Genetic Models Genomic Segment Genomics Goals Growth Heterozygote Human Human Chromosomes In Vitro Individual Intellectual functioning disability Interdisciplinary Study Link Mental Depression Modeling Molecular Morphogenesis Morphology Mus Mutation Myelin Neural Conduction Neuronal Plasticity Oligodendroglia Patients Penetrance Persons Phenotype Positioning Attribute Production Proliferating Role Schizophrenia Scientist Seizures Signal Transduction Small Interfering RNA Structural Congenital Anomalies Structural defect System Testing Therapeutic Time Tissues Work autism spectrum disorder brain cell clinical investigation clinical trial readiness cohort data communication data sharing data submission dysmyelination experimental study gene product genetic information high throughput screening human model improved in vitro Model in vivo induced pluripotent stem cell lymphoblastoid cell line member mosaic mouse model myelination neural neurotransmission phenotypic data processing speed programs response screening therapy development tool translational potential transmission process

项目摘要

ABSTRACT Suboptimal myelination of the brain, whether developmental or degenerative, has major ramifications on function. Abnormal myelin slows nerve conduction and signal synchronicity with consequences such as seizures, intellectual disability, autism and accelerated age-related cognitive decline. We have identified an approximately 1.6 megabase region of human chromosome 18q23 that when hemizygous results in a failure of myelin to develop normally. However, it is not yet known if the cause of this dysmyelination is due to haploinsufficiency of one of the gene products or a synergistic effect of more than one gene in the critical genomic region. In this proposal, we have created a team of both clinical and basic scientists to address this question. Together, we will acquire sufficient data to formulate a successful experimental system to define the cellular consequences of the causal genetic defect(s) at 18q23 on oligodendrocyte proliferation, maturation and myelin function both in mice and in human in vitro models. We will develop an integrated pipeline to perform rescue experimentation in human and mouse models that will lead to development of high throughput assays for drug screening experiments in which to test successful compounds on correcting or improving the dysmyelination defect at key stages of development. For this project, we will generate induced pluripotent stem cells (iPSC) from 3 individuals who are mosaic for a chromosome 18q23 deletion thereby creating sets of isogenic positive and negative control lines. From these we will derive myelinating cortical spheroid models to comprehensively evaluate for myelination abnormalities as compared to their controls with genomic background that differs only at the 18q23 locus. At the same time we will use siRNA silencing of the conserved 18q23 genes in mouse brain cells to define roles in myelinogenesis and compare to the myelin characteristics observed in the human 18q23- model. Correlation of the human and mouse data are essential in order to develop a live mouse model that recapitulates the human condition and can then be used for drug toxicity and effectiveness screening in combination with the human in vitro models. In turn, the longitudinal program of the Chromosome 18 Clinical Research Center maintains close contact with the largest cohort of individuals with chromosome 18 abnormalities, thus making it well positioned to inform interpretation of experimental results as well as conduct clinical trials based on findings from these results.

抽象的无论发育性还是退化性，大脑的次优髓样功能的影响。异常髓磷脂会减慢神经传导和信号同步性癫痫发作，智力残疾，自闭症和与年龄有关的后果认知能力下降。我们已经确定了人类的大约1.6兆瓦区域 18Q23染色体，当半合子导致髓磷脂正常发育时。但是，尚不清楚这种失常的原因是否是由一个单倍弥补引起的关键基因组区域中多个基因的基因产物或一种协同作用。在此提案中，我们建立了一个临床和基础科学家的团队来解决这个问题问题。一起，我们将获得足够的数据来制定成功的实验系统在少突胶质细胞上定义在18q23处的因果遗传缺陷的细胞后果在小鼠和人体体外模型中的增殖，成熟和髓磷脂功能。我们将开发集成管道以在人和小鼠模型中进行救援实验这将导致开发用于药物筛查实验的高通量测定法在关键阶段测试成功的化合物，以纠正或改善降解性缺陷发展。对于这个项目，我们将从3产生诱导的多能干细胞（IPSC）镶嵌为染色体18q23删除的个体，从而创建一组等源性正面和负面对照线。从这些中，我们将得出髓质的皮质球体模型与他们的对照相比，全面评估髓鞘异常基因组背景仅在18q23基因座上有所不同。同时，我们将使用sirna 在小鼠脑细胞中保守的18q23基因的沉默以定义骨髓生成中的作用并与在人类18q23模型中观察到的髓磷脂特征进行比较。相关性人类和鼠标数据对于开发概括的活鼠标模型至关重要人类状况，然后可用于药物毒性和有效性筛查与人类体外模型的结合。反过来，染色体的纵向程序 18临床研究中心与最大的人群保持着密切的联系染色体18异常实验结果以及基于这些结果的发现进行临床试验。