SZ-associated loci: Functional consequences and treatment opportunities

SZ 相关位点：功能后果和治疗机会

基本信息

批准号：
9920776
负责人：
Dimitrios Avramopoulos
金额：
$ 73.38万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-03 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9920776
关键词：
Affect Antipsychotic Agents Astrocytes Automobile Driving Biological Biological Process Buffers CRISPR/Cas technology Categories Cell Line Cell physiology Cells Clinical Communities Complement Data Defense Mechanisms Development Disease Equilibrium Female Gene Cluster Gene Expression Gene Expression Profile Genes Genetic Transcription Genetic Variation Genotype Goals Homozygote Human Intervention Knowledge Laboratories Lead Length Life Linkage Disequilibrium Maps Measurable Molecular Neuroglia Neurons Noise Organism Output Patients Pharmaceutical Preparations Pharmacologic Substance Pharmacology Phenotype Prevention Proteins Protocols documentation RNA Research Research Personnel Resource Sharing Resources Risk Role Schizophrenia Screening procedure Signal Transduction Specificity Technology Testing Variant brain cell cell type cost disease phenotype disorder risk experimental study follow-up gene function genetic association genetic signature genetic variant genome editing genome wide association study improved individualized medicine induced pluripotent stem cell insight male precision medicine response risk variant stem tool transcriptome transcriptome sequencing

项目摘要

Normal development and healthy life are the result of the coordinated function of gene networks that appropriately adjust their equilibrium as needed. Functional genetic variation can shift network equilibrium and under unfavorable circumstances make networks fail, leading to disease. Most common functional genetic variants have small effects at the organism level, however our and others' data suggest that they may have much larger effects on isolated cells, in the absence of the organism's buffering defense mechanisms. In cells changes can be more striking, the most immediate change being in the cell's transcriptional output. The transcriptional signature of a functional variant reflects the specific networks it disrupts and when studied across many variants can help identify intervention targets. We propose to study 10 SZ associated loci and identify their common networks and candidate pharmacological interventions through the following specific aims: 1) We will choose loci where one or few experiments can confidently achieve targeting the functional variant. We will edit the genome of one male and one female induced pluripotent stem cell (iPSc) line to generate homozygotes for the risk and non-risk allele. These will be a resource for the next aims and for sharing with others. 2) We will differentiate the iPSc to cortical neurons and to astrocytes and compare the transcriptomes of the two homozygotes that are otherwise isogenic. We will perform 20 locus specific transcriptome analyses per cell type (10 in male and 10 in female cells) and compare results. 3) We will analyze all loci together to identify gene clusters that similarly change their expression in response to many modified loci. We will perform exploratory analyses that may offer insights in the involvement of these clusters in disease risk, the best candidate cluster for follow up and the specific relationship of each cluster to clinical presentation. We will then do a first screen for complementary drug signatures utilizing public resources, follow up select compounds to verify complementarity in neurons and astrocytes, test for rescue of the SZ variant induced changes and identify possible male-female differences. At the end of the project we will have created the first resource of modified iPS cells carrying functionally confirmed SZ-risk alleles. We will have identified gene clusters reflecting signatures of network disruptions shared by many SZ loci. We will have determined the specificity each cluster contributes to the disease phenotype and identified candidate pharmacological interventions for further testing.

正常发育和健康生活是基因网络协调作用的结果根据需要适当调整它们的平衡。功能遗传变异可以改变网络平衡在不利的情况下会使网络失效，导致疾病。最常见的功能遗传变异在生物体水平上的影响很小，但是我们和其他人的数据表明它们可能具有在缺乏生物体缓冲防御机制的情况下，对孤立细胞的影响要大得多。在细胞中变化可能更加引人注目，最直接的变化是细胞的转录输出。这功能变体的转录特征反映了它破坏的特定网络以及研究时的情况跨越许多变体可以帮助确定干预目标。我们建议研究 10 个 SZ 相关基因座通过以下具体措施确定其共同网络和候选药理干预措施目标：1）我们将选择一个或几个实验可以自信地实现靶向功能的位点变体。我们将编辑一种雄性和一种雌性诱导多能干细胞 (iPSc) 系的基因组，以生成风险和非风险等位基因的纯合子。这些将成为下一个目标的资源与他人分享。 2) 我们将 iPSc 与皮质神经元和星形胶质细胞区分开来，并比较两个纯合子的转录组，否则是等基因的。我们将进行 20 个位点特异性对每种细胞类型（男性细胞 10 个，女性细胞 10 个）进行转录组分析并比较结果。 3）我们会一起分析所有基因座，以确定基因簇，这些基因簇同样会根据许多基因座的变化而改变其表达修饰基因座。我们将进行探索性分析，可能会提供有关这些集群参与情况的见解在疾病风险中，随访的最佳候选簇以及每个簇与临床的具体关系推介会。然后，我们将利用公共资源对补充药物特征进行首次筛选，请遵循选择化合物来验证神经元和星形胶质细胞的互补性，测试 SZ 变体的拯救诱发变化并识别可能的男女差异。在项目结束时我们将创建携带功能确认的 SZ 风险等位基因的改良 iPS 细胞的第一个资源。我们将已经确定反映许多 SZ 位点共享的网络中断特征的基因簇。我们将确定每个簇对疾病表型有贡献并确定候选药理学的特异性进一步测试的干预措施。