Project 1

项目1

基本信息

批准号：
9978135
负责人：
Dimitrios Avramopoulos
金额：
$ 42.42万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-12 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9978135
关键词：
16p 16p11.2 8p21 Ablation Address Adolescence Affect Alleles Antipsychotic Agents Autopsy Axon Behavioral Biological Biological Assay Biology Brain CRISPR/Cas technology Categories Cells Clinical Trials Code Collaborations Copy Number Polymorphism Custom Data Defect Denmark Development Disease Exons Exposure to FRAP1 gene Failure Forms Controls Functional disorder Funding Future Genes Genetic Genetic Population Study Genetic Transcription Genomics Glucocorticoids Growth Homeostasis Human Genetics In Vitro Knock-out Lesion Libraries Link LoxP-flanked allele Maps Measures Mediating Methods Microtubules Modeling Molecular Mus Mutation Neurons Pathogenicity Pathology Pathway interactions Patients Phenotype Physiological Proteins Psychotic Disorders Puberty Regulatory Element Reporter Resources Rest Schizophrenia Signal Transduction Stress Structural defect Structure Testing Transcript Transcriptional Regulation Translating Translations Untranslated RNA Validation Variant Work case control chromosome conformation capture cohort environmental stressor follow-up gene environment interaction genetic architecture genome wide association study improved in vivo loss of function loss of function mutation molecular phenotype mouse model mutant postnatal rare variant response restoration therapy design trait transcriptome transcriptome sequencing

项目摘要

Large-scale population genetic studies have begun to map the genetic architecture of schizophrenia (SZ). We now know that the genetic contribution of this multifactorial trait arises from a variety of lesions that include a) rare copy number variants (CNVs) of strong effect; b) common non-coding alleles of mild effect; and c) rare coding alleles that cluster in biological modules. Our recent studies have afforded us the opportunity to synthesize genetic, genomic, and functional studies to dissect the contribution of microtubule and ciliary dysfunction to SZ and to develop physiologically relevant assays to interrogate the effect of genes and alleles as a means of augmenting statistical power. Here, we will continue to focus on a specific biological module, the protein cluster that regulates microtubule function as it relates to axon/dendritic growth and ciliary function, and to dissect its contribution to SZ in terms of CNV pathomechanism; regulatory mutations; and rare alleles of large effect. We are uniquely placed to measure the contribution of this module to SZ. First, we will improve our understanding of the 16p11.2 CNV pathology, one of the most significant contributors to SZ; drawing from expertise both from our group as well as from Projects 2, 3 and Core C, we will test the contributory hypothesis for KCTD13, a gene for which we and others have amassed strong, but indirect, genetic and functional evidence of involvement. Second, we will assay the downstream effect of changes in four microtubule genes, including changes of regulatory elements, on the rest of the transcriptome and on SZ associated genes and pathways (with Project 2 and Core B). Finally, we will implement our in vivo assays to interpret sequencing data on candidate SZ genes in order to establish the direction of effect of candidate pathogenic alleles and to measure the overall burden of these loci to SZ. Taken together, our work, upon intersection with the studies of the other Center components, will inform the genetic contribution and the biological mechanisms of microtubule (dys)function to discrete aspects of SZ pathology and potentially help improve the design of treatment paradigms and future clinical trials.

大规模群体遗传学研究已经开始绘制精神分裂症（SZ）的遗传结构图。我们现在知道这种多因素性状的遗传贡献源于多种病变，包括：罕见的强效拷贝数变异（CNV）； b) 具有轻微影响的常见非编码等位基因； c) 稀有编码聚集在生物模块中的等位基因。我们最近的研究使我们有机会综合遗传、基因组和功能研究来剖析微管和纤毛的贡献 SZ 功能障碍并开发生理相关测定法来询问基因和等位基因的影响作为增强统计能力的一种手段。在这里，我们将继续关注一个特定的生物模块，调节微管功能的蛋白质簇，因为它与轴突/树突生长和纤毛功能有关，以及从 CNV 病理机制角度剖析其对 SZ 的贡献；调节突变；和罕见的等位基因作用大。我们处于独特的地位来衡量该模块对 SZ 的贡献。首先，我们将改进我们的了解 16p11.2 CNV 病理学，这是 SZ 最重要的贡献者之一；借鉴自凭借我们团队以及项目 2、3 和核心 C 的专业知识，我们将测试贡献假设对于 KCTD13，我们和其他人已经积累了强大但间接的遗传和功能基因参与的证据。其次，我们将测定四个微管基因变化的下游影响，包括转录组其余部分和 SZ 相关基因的调控元件的变化以及途径（项目 2 和核心 B）。最后，我们将实施体内测定来解释测序候选 SZ 基因的数据，以确定候选致病等位基因的作用方向并测量这些位点对 SZ 的总体负担。总而言之，我们的工作与研究相交叉中心的其他组成部分将告知微管的遗传贡献和生物学机制功能（功能障碍）对 SZ 病理学的各个方面产生影响，并可能有助于改进治疗设计范式和未来的临床试验。