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Optimizing Models of Non-Coding Genetic Risk in Age-Related Macular Degeneration

年龄相关性黄斑变性非编码遗传风险模型的优化

基本信息

批准号：
10343475
负责人：
TIMOTHY JOEL CHERRY
金额：
$ 49.23万
依托单位：
SEATTLE CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-01 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10343475
关键词：
10q26 Address Affect Age Age related macular degeneration Animal Model Automobile Driving Biological Models Biology Blindness Cell Culture System Cell physiology Cells DNA Sequence Data Development Disease Elements Enhancers Evolution Experimental Models Gene Expression Genes Genetic Genetic Risk Genetic Variation Genetic study Goals Histology Human In Vitro Inherited Knock-out Knockout Mice Knowledge Late-Onset Disorder Maps Methods MicroRNAs Modeling Mus Mutation Organoids Other Genetics Outcome Persons Public Health Regulation Regulatory Element Research Retina Retinal Diseases Retinal Pigments Risk Risk Factors Role Shapes Structure Structure of retinal pigment epithelium Study models System Testing Tissues Transgenic Mice United States Untranslated RNA Vision Vision Disorders Visual Work cell type experimental study genetic analysis genetic risk factor genome wide association study improved in vitro Model in vitro testing in vivo induced pluripotent stem cell insight macula mouse genome mouse model multiple omics novel risk variant single-cell RNA sequencing therapy development tissue culture

项目摘要

PROJECT SUMMARY/ABSTRACT Genome-wide association studies (GWAS) and other genetic analyses consistently implicate non-coding cis- regulatory elements (CREs) in age-related macular degeneration (AMD). However, the contribution of CREs to the risk of developing AMD remains poorly understood because the function these elements has not yet been directly tested. The barrier for testing AMD-associated CREs is in part due to the challenge of developing experimentally validated model systems. CREs can be cell-type-specific and are not necessarily conserved between humans and model organisms. It therefore remains unclear which CREs may be studied in vivo in transgenic mice versus which require an in vitro human cell system. This gap in knowledge is a significant obstacle toward understanding the genetic regulation of normal human vision and to understanding the contribution of specific CREs to AMD. The long-term goal for our research is to understand how genetic variation within CREs shapes the structure and function of the retina and contributes to the risk of developing AMD and other disorders of vision. The focused objective of this proposal is to optimize and validate model systems for studying the function of AMD-associated CREs. The central hypothesis driving this work is that some AMD- associated CREs will be conserved between humans and mice due to their functional importance in vision. Other CREs may be human-specific due to their essential roles in the macula, a part of the retina that is not present in mice. In each of these cases, one or more optimal systems will be required to understand the function of each AMD-associated CRE. To test this hypothesis, we are pursuing the following specific aims: 1) Determine the functional conservation of AMD-associated CREs between humans and mice. 2) Test the function of a specific CRE that is known to be conserved between humans and mice from our preliminary studies in a newly developed mouse knockout model. 3) Test the requirement of human-specific CREs that are among the leading contributors to AMD risk, in induced human retinal tissue cultures. Together these experiments will enable discovery of genetic contributions to human vision and inherited visual diseases that have thus far been inaccessible using current methods.

项目总结/文摘