Functional Analysis of the 22q11.2 schizophrenia susceptibility genes

22q11.2精神分裂症易感基因的功能分析

基本信息

批准号：
8584869
负责人：
MARIA KARAYIORGOU
金额：
$ 73.71万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8584869
关键词：
22q11.2 Accounting Adolescence Animal Model Architecture Area Attention Autistic Disorder Bacterial Artificial Chromosomes Behavioral Biogenesis Biological Bipolar Disorder Brain Cataloging Catalogs Child Chromosomes Cognitive Cognitive deficits Comparative Study DLG4 gene Data Development Diagnostic Disease Drug Targeting Event Exhibits Functional disorder Funding Future General Population Genes Genetic Genomics Grant Heterogeneity Human Impaired cognition Individual Investigation Label Link Mediating Mental disorders MicroRNAs Modeling Molecular Mus Mutant Strains Mice Mutation Neurobiology Neurodevelopmental Disorder Neurons Nucleotides Pathogenesis Patients Pattern Penetrance Phenotype Play Predisposition Prefrontal Cortex Property Proteins Recurrence Research Research Design Risk Risk Factors Role Schizophrenia Series Short-Term Memory Structure Susceptibility Gene Symptoms Synapses Techniques Testing Transgenes Variant Work axon growth clinical phenotype cognitive function cohort design emerging adult executive function genetic variant genome wide association study genome-wide improved induced pluripotent stem cell insertion/deletion mutation insight interest microdeletion mouse model mutant neural circuit novel therapeutics palmitoylation public health relevance

项目摘要

DESCRIPTION (provided by applicant): It is now evident that many cases of psychiatric and neurodevelopmental disorders, as well as disorders of cognitive function, are due to highly penetrant, rare genetic variants. 22q11.2 deletion is a prominent example of such a variant. Carriers of deletions in chromosome 22q11.2, which predominantly occur de novo, exhibit a spectrum of cognitive deficits and develop schizophrenia in adolescence or early adulthood at a rate of 25-30%. Recurrent 22q11.2 deletions account for as many as 1-2% of cases of sporadic schizophrenia in the general population. Because of its leading role in the genetic landscape of psychiatric disease and cognitive dysfunction, functional analysis of the 22q1.2 deletion holds great promise for providing the biological insights necessary for development of new treatments for these conditions. In this project, we propose to study the impact of 22q11.2 deletions on neuronal structure and function in exquisite depth. Our proposed research focuses on this highly significant problem using state-of-the-art techniques, reliable animal models, and patient- derived neurons, and is designed to improve our understanding of the chain of events leading from the mutation, through its effects on neural cells and circuits, to clinical phenotype and inform the development of new therapeutics. A major aspect of our effort will be to implement carefully controlled translational paradigms to test many of the alterations that we find in mouse models in neurons from patients. Along these lines, we propose to pursue detailed comparative studies between human and mouse, using cortical neurons derived from induced pluripotent stem cells (iPSCs) from humans carrying the 22q11.2 deletion. The strength of this approach is undeniable since it will allow in-depth analysis at the level of the individual neuron and synapse, which are otherwise inaccessible in patients.

描述（由申请人提供）：现在很明显，许多精神病和神经发育障碍的病例以及认知功能的疾病都是由于高度渗透性，稀有的遗传变异造成的。 22Q11.2删除是这种变体的重要示例。染色体22q11.2中主要发生的染色体缺失的载体表现出一系列认知缺陷，并在青春期或成年早期以25-30％的速度发展出精神分裂症。经常性的22q11.2缺失占普通人群零星精神分裂症病例的1-2％。由于其在精神疾病和认知功能障碍的遗传景观中的主要作用，对22q1.2缺失的功能分析具有巨大的希望，这是提供为这些疾病开发新疗法所必需的生物学见解。在这个项目中，我们建议研究22q11.2缺失对神经元结构和功能的影响。我们提出的研究重点是使用最新的技术，可靠的动物模型和患者衍生的神经元，旨在提高我们对突变事件的理解，通过其对神经细胞和电路的影响，临床表型和新疗法发展的临床表型和信息。我们努力的一个主要方面是实施精心控制的翻译范式，以测试我们在患者的神经元中的小鼠模型中发现的许多变化。沿着这些线条，我们建议使用来自携带22q11.2缺失的人类诱导多能干细胞（IPSC）的皮质神经元进行详细的比较研究。这种方法的强度是不可否认的，因为它将在单个神经元和突触的水平上进行深入分析，否则在患者中无法访问。