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Molecular mechanisms and genetic drivers of reciprocal genomic disorders

相互基因组疾病的分子机制和遗传驱动因素

基本信息

批准号：
10224767
负责人：
MICHAEL E TALKOWSKI
金额：
$ 68.21万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
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：
2018-09-15 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10224767
关键词：
16p11.2 22q11.2 Ablation Affect Animal Model Architecture Biological Models CRISPR/Cas technology CRKL gene Cell Line Cell model Child Clustered Regularly Interspaced Short Palindromic Repeats Companions Complex Computer Models Critical Pathways DNA Sequence Alteration Data Defect Development Diagnosis Disease Disease model Dose Engineering Gene Combinations Gene Expression Gene Expression Profile Genes Genetic Genetic Transcription Genome Genomic Segment Genomic approach Genomics Goals Grant Human In Vitro Individual Kidney Mediating Modeling Molecular Molecular Computations Molecular Profiling Mus Nature Neurodevelopmental Disorder Neurons Pathogenicity Pathway interactions Phenotype Population Prevention Process Recurrence Reproducibility Resources Specificity Syndrome Technology Testing Therapeutic Tissues Validation Zebrafish base common treatment comorbidity congenital anomaly disability dosage gene discovery genome editing homologous recombination improved in vivo in vivo Model induced pluripotent stem cell innovation insight microdeletion molecular phenotype mouse model nerve stem cell neuropsychiatry novel relating to nervous system screening therapeutic target trait transcriptome

项目摘要

ABSTRACT Reciprocal genomic disorders (RGDs) involve recurrent microdeletion and microduplicaton of identical genomic segments. RGDs are mediated by non-allelic homologous recombination (NAHR) and are collectively among the most common recurrent genetic causes of neurodevelopmental disorders (NDD) and congenital anomalies in humans. Given that the impact of RGDs is usually early in development, these disorders disproportionately affect children and often result in lifelong disabilities. Discovery of the genes the molecular consequences of RGDs and the genes that underlie components of these disorders would therefore represent exceptionally high priority targets for mechanistic studies and therapeutic targeting across a spectrum of Mendelian and complex disorders. Our Preliminary Data suggest that an integrated in vitro and in vivo molecular and computational genomics approach using cellular and animal modeling can identify molecular signatures associated with RGDs and the genetic drivers of aberrant phenotypes and dysregulated networks. In these studies, we will first define the gene expression profiles and cellular phenotypes associated with microdeletion and microduplication of the 8-12 most prevalent RGD regions in neural derivatives from isogenic induced pluripotent stem cell (iPSC) lines. We will accomplish this using a CRISPR/Cas9 genome editing approach we recently developed that targets the flanking segmental duplications and mimics NAHR-mediated mechanisms in humans (Aim 1). We will then seek the specific genes associated with RGD-associated phenotypes using high-throughput driver gene screening in zebrafish (Aim 2) to evaluate all individual genes and pairwise interactions within RGD regions. In Aim 3 we will then seek to validate these predicted drivers and determine their impact in diverse neuronal lineages and across mouse tissues. These studies will thus follow a framework our investigative team has previously used to identify genetic drivers of non-recurrent microdeletion syndromes and several RGD regions, including 16p11.2 RGD, and apply innovative approaches and technologies to enable us to conduct these studies at scale and compare signatures across RGDs. At their conclusion, tehse analyses will define the molecular signatures of the most common RGDs in humans, the genes that drive specific components of these signatures, their tissue specificity, and the capacity to rescue the strongest signatures through dosage manipulation in vitro and in vivo.

摘要