Connecting Rare Mutations to Common Pathways

将罕见突变与常见途径联系起来

基本信息

批准号：
10632003
负责人：
JEFFREY D MILBRANDT
金额：
$ 31.5万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-28 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10632003
关键词：
ATAC-seq Affect Apoptosis Binding Biological Assay Biological Markers Biological Models Brain Cell Line Cell model Cells Cellular Assay Child Chromatin Clinical DNA Footprint Development Diagnosis Disease Emotional Environmental Risk Factor Gene Expression Gene Expression Profile Genes Genetic Heterogeneity Genetic Transcription Genetic study Genome Genome engineering Genomics Genotype Goals Human Image Individual Induced pluripotent stem cell derived neurons Intellectual and Developmental Disabilities Research Centers Intellectual functioning disability Length Measures Methods Molecular Morphology Mutation Neurobiology Neuronal Differentiation Neurons Pathogenesis Pathogenicity Pathology Pathway interactions Patients Performance Phase Phenotype Population Process Proliferating Protocols documentation Repression Research Project Grants Resources Role Site Societies Therapeutic Intervention Time Transcriptional Regulation Universities Variant Washington chromatin remodeling clinical translation developmental disease effective therapy endophenotype excitatory neuron experimental study gene repression genetic risk factor genetic variant induced pluripotent stem cell inhibitory neuron insight knock-down loss of function multiple omics nerve stem cell neurite growth neurodevelopment neuroimaging new therapeutic target novel patient subsets phenotypic data rare variant response single-cell RNA sequencing stem cell differentiation synaptogenesis technology development therapeutically effective

项目摘要

Research Project, Project Summary Intellectual and developmental disabilities (IDDs) exact a heavy emotional and financial toll on society, affecting an estimated 1 in 6 children in the US. Developing effective therapeutic interventions to treat IDD is a challenging problem because a large number of environmental and genetic risk factors contribute to these diseases. Indeed, IDD-associated genetic variants have been identified in more than 700 genes, but each variant is present in only a small number of patients, and our understanding of how these variants contribute to the disease is limited. This high degree of genetic heterogeneity and lack of mechanistic insights confound efforts to develop effective therapies to treat IDD. If individual mutations can be grouped by shared molecular pathways, then targeting these pathways may be efficacious in large subsets of patients. The overall goal of our proposal is to develop CRANIUM, a platform that will read out the genomic, transcriptional, and neuronal phenotypic signatures of IDD genes to reveal common pathways disrupted by IDD-associated mutations.

研究项目、项目概要智力和发育障碍（IDD）给社会带来沉重的情感和经济损失，影响据估计，美国有六分之一的儿童。开发有效的治疗干预措施来治疗 IDD 是一项具有挑战性的工作问题是因为大量环境和遗传风险因素导致这些疾病。的确，已在 700 多个基因中鉴定出与 IDD 相关的遗传变异，但每种变异仅存在于少数患者，我们对这些变异如何导致疾病的了解有限。这高度的遗传异质性和缺乏机制见解阻碍了开发有效药物的努力治疗 IDD 的疗法。如果单个突变可以通过共享的分子途径进行分组，那么靶向这些途径可能对大部分患者有效。我们提案的总体目标是发展 CRANIUM，一个可以读取 IDD 基因组、转录和神经元表型特征的平台基因来揭示 IDD 相关突变破坏的常见途径。