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，许多精神和神经发育障碍以及认知功能障碍的病例是由高度渗透的罕见遗传变异引起的。 22q11.2 缺失是此类变异的一个突出例子。染色体 22q11.2 缺失的携带者主要是从头发生的，表现出一系列认知缺陷，并在青春期或成年早期以 25-30% 的比例患上精神分裂症。复发性 22q11.2 缺失占普通人群散发性精神分裂症病例的 1-2%。由于其在精神疾病和认知功能障碍的遗传景观中发挥主导作用，22q1.2 缺失的功能分析有望为开发针对这些疾病的新疗法提供必要的生物学见解。在这个项目中，我们建议深入研究 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利用最先进的技术、可靠的动物模型和患者来源的神经元来解决这个非常重要的问题，旨在通过突变对神经细胞和回路，以了解临床表型并为新疗法的开发提供信息。我们努力的一个主要方面是实施仔细控制的翻译范例，以测试我们在小鼠模型中发现的来自患者神经元的许多改变。沿着这些思路，我们建议使用源自携带 22q11.2 缺失的人类诱导多能干细胞 (iPSC) 的皮层神经元，对人类和小鼠进行详细的比较研究。这种方法的优势是不可否认的，因为它将允许在单个神经元和突触水平上进行深入分析，这是患者无法接触到的。