Name:
Institution:
Type:
PI
Grant Award Details
Development of a stem-cell based approach to interpret global effects of genetic variants contributing to neurodevelopmental disease risk
Grant Type:
Grant Number:
DISC0-13808
Project Objective:
- To establish a high throughput single cell base editing approach (scBE-seq) in hiPSC, and apply it to the interrogation of pathogenicity of a large number of SNVs introduced into 2 genes known to play a role in neurodevelopmental diseases.
Investigator:
Disease Focus:
Neurological Disorders
Rett's Syndrome
Human Stem Cell Use:
iPS Cell
Award Value:
$1,518,982
Status:
Active
Grant Application Details
Application Title:
- Development of a stem-cell based approach to interpret global effects of genetic variants contributing to neurodevelopmental disease risk
Public Abstract:
Research Objective
We are developing a strategy to characterize the disease-relevance of hundreds of mutations across diverse genetic backgrounds using stem cells
Impact
Understanding how mutations impact cellular function can identify treatments for genetic diseases, but currently less than 1% of identified mutations have a known function.
Major Proposed Activities
- Identify optimal conditions for SNV library introduction in hiPCSs and characterize the global impact of individual mutations in ERCC2 and MECP2 on transcription, chromatin state, and mutational rates
- Develop a computational pipeline to design SNV libraries and analyze data from our method, scBE-seq
- Employ scBE-seq to study the impact of libraries of mutations in ERCC2 and MECP2 during the in vitro neurodifferentiation of hiPSCs into cortical organoids
- Analyze scBE-seq data and compare with orthogonal datasets for clinical interpretation of genetic variation
Statement of Benefit to California:
An overrepresentation of European human genome sequencing data has generated inequities in regenerative and precision medicine efforts. We propose here to develop a more equitable strategy to characterize the disease-relevance of mutations from diverse populations. Our project will identify new preventative strategies, treatments, and cures for genetic diseases applicable to a variety of ethnic groups, and will therefore benefit the State of California and its highly ethnically diverse citizens.
