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.

正常发展和健康的生活是基因网络协调功能的结果根据需要适当调整其平衡。功能性遗传变异可以改变网络平衡，并在不利的情况下，网络失败，导致疾病。最常见的功能遗传变体在生物层的影响很小，但是我们和其他人的数据表明它们可能有在没有生物体缓冲防御机制的情况下，对孤立细胞的影响更大。在细胞中变化可能更引人注目，最直接的变化是单元的转录输出。这功能变体的转录签名反映了它破坏的特定网络和研究在许多变体中，可以帮助识别干预目标。我们建议研究10 sz相关的基因座和通过以下特定确定他们的共同网络和候选药理干预措施目的：1）我们将选择一个或几个实验可以自信地实现功能的基因座变体。我们将编辑一个雄性和一名雌性诱导多能干细胞（IPSC）系的基因组为风险和非风险等位基因生成纯合子。这些将是下一个目标和与他人分享。 2）我们将IPSC与皮质神经元和星形胶质细胞区分开并进行比较两个纯合子的转录组，否则是同基因的。我们将执行20个基因座转录组分析每种细胞类型（男性为10，女性细胞为10），并比较结果。 3）我们会的一起分析所有基因座，以识别基因簇，这些基因簇对许多人的表达方式类似地改变了其表达修改的基因座。我们将执行探索性分析，这些分析可能会在这些集群的参与中提供见解在疾病风险中，最佳的候选群集进行跟进以及每个集群与临床的特定关系推介会。然后，我们将使用公共资源进行第一个屏幕，以进行互补的药物签名，请关注提高精选化合物以验证神经元和星形胶质细胞中的互补性，测试SZ变体诱导的变化并确定可能的男女差异。在项目结束时，我们将创建携带功能确认的SZ风险等位基因的修改的IPS单元的第一个资源。我们将确定基因簇反映了许多SZ基因座共享网络中断的特征。我们将确定特异性每个簇有助于疾病表型并确定候选药理进一步测试的干预措施。