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Unraveling the molecular pathology of retinal degeneration through single cell genomics

通过单细胞基因组学揭示视网膜变性的分子病理学

基本信息

批准号：
10624311
负责人：
Radha Ayyagari
金额：
$ 68.66万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10624311
关键词：
Ablation Affect Animal Model Architecture Biological Assay Blindness CRISPR/Cas technology Cell Culture Techniques Cell Nucleus Cell model Cells Choroid Chromatin Code Collaborations Computer Analysis DNA DNA methylation profiling Data Data Set Development Disease Disease model Enhancers Epigenetic Process Female Gene Mutation Genes Genetic Genetic Models Genome Genomics Goals Human Human Genome Individual Inherited Japan Joints Left Maps Methodology Modeling Molecular Multiomic Data Mutation Mutation Detection Netherlands Nucleic Acid Regulatory Sequences Nucleotides Outcome Outcome Study Pakistan Pathologic Pathology Patients Peripheral Physiological Positioning Attribute RNA RNA Splicing Recording of previous events Regulatory Element Research Research Personnel Resolution Resources Retina Retinal Degeneration Retinal Diseases Retinal Dystrophy Sequence Analysis Site Structure Structure of retinal pigment epithelium Switzerland System Testing Time Tissue Sample Tissues Transcript Untranslated RNA Validation Variant base editing candidate validation causal variant cell type epigenomics genetic pedigree genome sciences genome sequencing human tissue improved in vivo induced pluripotent stem cell inherited retinal degeneration innovation insight invention macula male methylome molecular pathology mouse model multidisciplinary multiple omics novel therapeutics stable cell line tool transcriptome whole genome

项目摘要

Abstract: The overarching goal of this proposal is to understand the molecular pathology of inherited retinal degeneration (IRD) by (a) generating maps of human retinal cell type-specific regulatory elements, (b) utilizing these maps to identify non-coding IRD causative mutations within retinal regulatory elements, and (c) gaining insight into the molecular underpinnings of pathological non-coding IRD mutations using cellular and animal models. IRDs are the most common cause of irreversible blindness in young individuals affecting 1 in 3000 individuals. Mutations in coding and splice site sequences in known IRD associated genes contribute to about 60%-65% of cases while the remaining 40%-35% of cases are currently unresolved. Mutations in non-coding or regulatory sequences are suggested to be responsible for a large proportion of these unresolved cases. Although the ENCODE and Roadmap Epigenomics projects have generated detailed maps of regulatory elements for the majority of body tissues, retina is left out. Lack of these maps is a major limitation in identifying IRD causative mutations involving regulatory sequences in retinal cells. We have analyzed the whole genome sequence (WGS) of 125 pedigrees with IRD; of these, 49 remain unresolved with no candidate causative nucleotide changes or structural variants (SVs) in coding or splice site sequences. This leads us to hypothesize the involvement of non-coding variants in pathology. We also have access to more than 391 additional IRD pedigrees that remained unresolved after WGS analysis. In this application we propose to test the hypothesis that non-coding sequence changes are involved in IRD pathology for the majority of these unresolved pedigrees. We will conduct the following studies: Aim 1, establish human retinal cell type specific maps of regulatory elements using innovative single cell genomics methodologies we developed, Aim 2, rank prioritize candidate causative variants using the retinal cell type-specific regulatory element maps and WGS of unresolved pedigrees, Aim 3, validate the impact of high ranking non-coding candidate disease causing variants in the context of the genome architecture of retinal cell types by developing patient iPSC-derived retinal cell models and mouse models. These studies will result in the establishment of retinal cell type-specific high-resolution multi-omic maps and will potentially identify, for the first time, non-coding variants involved in the pathology of IRD. The outcomes of these studies will (1) significantly enhance our understanding of the architecture of retinal cell type-specific regulatory networks, (2) reveal the molecular pathology underlying IRD, (3) establish a highly valuable, publicly-available data set of cis-regulatory elements relevant to retinal degenerative diseases as a resource for retinal disease research, (4) improve mutation detection in patients, and (5) facilitate discovery and development of novel therapies for IRD. We have assembled a multidisciplinary team of outstanding investigators with expertise in epigenetics (Ren), genome sciences (Frazer) and IRD genetics and disease modeling (Ayyagari) who are well positioned to complete this ambitious project.

文摘:

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Single cell RNA sequencing confirms retinal microglia activation associated with early onset retinal degeneration.

DOI：
10.1038/s41598-022-19351-w
发表时间：
2022-09-10
期刊：
SCIENTIFIC REPORTS
影响因子：
4.6
作者：
Kumari, Asha;Ayala-Ramirez, Raul;Zenteno, Juan Carlos;Huffman, Kristyn;Sasik, Roman;Ayyagari, Radha;Borooah, Shyamanga
通讯作者：
Borooah, Shyamanga

Role of H3K4 monomethylation in gene regulation.