Center for Modeling Non-Coding Disease Variants: Disease Modeling Project

University Of California-Irvine, Irvine CA

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT: DISEASE MODELING PROJECT The aim of Disease Modeling Core is to advance our understanding of non-coding disease variants by generating and disseminating knock-in mouse models. This project addresses a critical gap in genomic research by focusing on the functional characterization of variants affecting non-coding regulatory elements, such as enhancers, silencers, alternative promoters and others, which play crucial roles in gene expression regulation and disease pathogenesis. The core will employ a novel dual-enSERT transgenic technology to classify non-coding variants as CIS or TRANS regulatory elements. This classification is essential for subsequent knock-in analysis and will help prioritize variants for further study. Over the grant period, the core aims to create transgenic and knock-in models for approximately 100 prioritized variants, encompassing various regulatory types to maximize the identification of functional variants and broaden the scope of the study. In Aim 1, the core will utilize a unique dual-enSERT transgenic technology to assess wild-type and variant cis-regulatory activity in live mice simultaneously. This approach will help establish the functional significance of disease variants within enhancer regions and inform subsequent knock-in studies. In Aim 2 we will generate a panel of disease variant knock-in mice to determine the in vivo functional significance of prioritized non-coding variants and provide a valuable resource for the scientific community. These models will undergo standardized phenotyping, including gene expression analysis, anatomical and pathological assessments, and integration with patient-derived data. The Disease Modeling Core will collaborate closely with the Bioinformatics Core, which will prioritize active non- coding variants for modeling. Additionally, the core will work with the Service Core to ensure efficient distribution of the variant knock-in mouse models. This project represents a significant step forward in bridging technology and physiology to tackle one of the most challenging quests of the genomic era: identifying non-coding variants that "matter" in a sea of potential ones. By focusing on active and conserved variants and employing innovative in vivo screening techniques, the Disease Modeling Core aims to provide crucial insights into the mechanistic and physiological roles of non-coding variants in disease. The resulting mouse models and associated data will serve as a valuable resource for researchers studying various diseases and will contribute to our understanding of gene regulation and disease pathogenesis.