Project 2

项目2

基本信息

批准号：
8080398
负责人：
NICHOLAS KATSANIS
金额：
$ 21.67万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-01 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8080398
关键词：
Affect Alleles Area Behavior Behavioral Binding Biological Assay Candidate Disease Gene Cells Centrosome Code Collaborations Collection Data Defect Development Disease Electroporation Epidemiologic Studies Etiology European Family Gene Proteins Genes Genetic Genetic Markers Genetic Predisposition to Disease Genotype Haplotypes Heterogeneity Hybrids In Vitro Laboratories Lead Maps Modeling Mus Mutation Neurons Nonsense Mutation Open Reading Frames Pathogenesis Pathway interactions Patients Phenocopy Phenotype Predisposition Proteins Publishing RNA Interference Recruitment Activity Role Schizophrenia Series Structure Susceptibility Gene System Testing Therapeutic Variant Work adult neurogenesis axon growth case control cell motility cohort combinatorial expectation functional genomics in vivo insight kinetosome loss of function loss of function mutation member migration mouse model mutant neurodevelopment novel proband programs protein function success

项目摘要

Schizophrenia (SZ) is a common disorder of largely obscure etiopathology. Epidemiological studies have highlighted the strong influence of genetic susceptibility on the development of the disease, which, in turn, raised the expectation that the identification of susceptibility loci will illuminate the causative cellular pathways. Despite substantial effort, success in this area has been relatively modest. Although numerous studies have mapped potential SZ loci, the number of replicated associations remains scarce. Moreover, even for bona fide SZ genes, the causative alleles remain elusive. Although there are many reasons for this, the most poignant confounding hurdle is the combination of genetic and allelic heterogeneity. Recent data by us and our collaborators, as well as the breadth of expertise in this Program offers the unique opportunity to approach SZ genetics from a combinatorial genetics and functional strategy. Together with colleagues from the proposed Center, we have shown that members of the pericentriolar matrix (centrosome, basal body) contribute alleles to the pathogenesis of psychiatric illness by virtue of loss of function defects that perturb the structure of the centrosome and affect bioth developmental and adult neurogenesis. As part of the Program, we will extend these findings in three ways. We will focus first on PCM1, a protein which, together with Project 1, we have shown to bind to DISC1 and to harbor loss of function mutations in SZ patients. To extend these observations, we will collaborate with Core C and screen a large SZ cohort and identify all coding variants likely detrimental to gene and protein function; these will be tested functionally in a combination of in vivo and in vitro systems drawing from expense both from our group, as well as from Projects 1 and 3 as well as Core B. Second, our data suggest that PCM1 null alleles render susceptibility to SZ; we will model this by ablating (both globally and conditionally) PCM1 in mice and assaying for any anatomical and behavior phenotypes. Finally, we will extend out studies to a series of novel pericentriolar proteins identified in the lab and assay a) whether suppression of these phenocopies the in vitro and in vivo phenotypes of PCM1 and DISC1; and b) whether alleles and/or haplotypes in these loci are associated with SZ (with Core C). These studies, together with the other Center groups, will enhance our understaning of the etiopathology of SZ and will provide both new genetic markers and potential therapeutic pathways.

精神分裂症（SZ）是一种常见疾病，其病因病理学基本上不为人所知。流行病学研究有强调了遗传易感性对该疾病发展的强烈影响，反过来，人们期望易感位点的鉴定将阐明致病细胞途径。尽管付出了巨大的努力，但该领域的成功相对有限。虽然数量众多研究已经绘制了潜在的 SZ 位点，但重复关联的数量仍然很少。而且，即使对于真正的 SZ 基因，致病等位基因仍然难以捉摸。虽然造成这种情况的原因有很多，最令人痛苦的混杂障碍是遗传异质性和等位基因异质性的结合。最新数据由我们和我们的合作者以及该计划中广泛的专业知识提供了独特的机会从组合遗传学和功能策略研究 SZ 遗传学。与来自的同事一起拟议的中心，我们已经证明了中心粒周围基质（中心体，基底体）的成员通过扰乱功能缺陷的丧失等位基因对精神疾病的发病机制做出贡献中心体的结构并影响生物发育和成人神经发生。作为计划中，我们将以三种方式扩展这些发现。我们首先关注 PCM1，这是一种蛋白质，它与通过项目 1，我们已证明与 DISC1 结合并在 SZ 患者中隐藏功能丧失突变。到扩展这些观察结果，我们将与 Core C 合作，筛选一个大型 SZ 队列并确定所有可能对基因和蛋白质功能有害的编码变异；这些将在一个体内和体外系统的结合，费用来自我们的团队以及来自项目 1 和 3 以及核心 B。其次，我们的数据表明 PCM1 无效等位基因使易感性深圳；我们将通过（全局和有条件地）消融小鼠中的 PCM1 并检测任何解剖学和行为表型。最后，我们将研究扩展到一系列新颖的中心粒周围在实验室和测定中鉴定的蛋白质 a) 是否抑制这些表型在体外和体内 PCM1和DISC1的表型； b) 这些基因座中的等位基因和/或单倍型是否与 SZ（带有核心 C）。这些研究与其他中心小组一起，将加深我们对 SZ 的病因病理学并将提供新的遗传标记和潜在的治疗途径。