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.

项目概要/摘要全基因组关联研究（GWAS）和其他遗传分析一致表明非编码顺式年龄相关性黄斑变性（AMD）中的调节元件（CRE）。然而，商业地产的贡献人们对患 AMD 的风险仍知之甚少，因为这些元素的功能尚未明确直接测试了。测试 AMD 相关 CRE 的障碍部分是由于开发的挑战经过实验验证的模型系统。 CRE 可以是细胞类型特异性的，并且不一定是保守的人类与模式生物之间。因此，尚不清楚哪些 CRE 可以在体内进行研究转基因小鼠与需要体外人类细胞系统的小鼠相比。这种知识差距是一个重大的差距理解正常人类视觉的基因调控和理解特定 CRE 对 AMD 的贡献。我们研究的长期目标是了解遗传变异如何 CRE 内的 CRE 塑造视网膜的结构和功能，并增加患 AMD 和其他视力障碍。该提案的重点目标是优化和验证模型系统研究 AMD 相关 CRE 的功能。推动这项工作的核心假设是一些 AMD- 由于相关的 CRE 在视觉中具有重要的功能，因此它们在人类和小鼠之间将是保守的。其他 CRE 可能是人类特异性的，因为它们在黄斑中发挥重要作用，黄斑是视网膜的一部分，但在视网膜中不存在。老鼠。在每一种情况下，都需要一个或多个最佳系统来了解每个系统的功能 AMD 相关的 CRE。为了检验这一假设，我们追求以下具体目标：1）确定人类和小鼠之间 AMD 相关 CRE 的功能保护。 2）测试特定功能根据我们在新开发的一项研究中的初步研究，已知 CRE 在人类和小鼠之间是保守的小鼠基因敲除模型。 3) 测试主要贡献者中针对人类的 CRE 的要求在诱导人视网膜组织培养中，AMD 风险。这些实验一起将能够发现遗传对人类视力和遗传性视觉疾病的贡献迄今为止无法通过使用目前的方法。