Identification of the specific risk allele responsible for oxidative stress in ARMS2/HTRA1-related AMD

鉴定导致 ARMS2/HTRA1 相关 AMD 氧化应激的特定风险等位基因

基本信息

批准号：
10707203
负责人：
Jose Luis McFaline-Figueroa
金额：
$ 40.87万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
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：
2022-09-30 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10707203
关键词：
10q Address Adult Affect Age related macular degeneration Alleles Anti-Inflammatory Agents Antioxidants Area Biology of Aging Cell Line Cell Proliferation Cells Choroid Chromosomes Clustered Regularly Interspaced Short Palindromic Repeats Coculture Techniques Complement Factor H Cultured Cells Disease Disease model Elderly Environment Etiology Eye Foundations Genes Genetic Risk Genomics Genotype High temperature of physical object Human Genome Immune Immunologics Individual Inflammatory Intervention Late-Onset Disorder Link Mediating Metabolic Methods Microglia Modeling Molecular Biology Mutation New York Outcome Oxidative Stress Pathogenesis Patients Peptide Hydrolases Predisposition Recording of previous events Research Retina Retinal Diseases Risk Risk Factors SOD2 gene Serine Single Nucleotide Polymorphism Structure of retinal pigment epithelium Testing Thrombospondin 1 Transcript Transforming Growth Factor beta Variant age related aged cell age disease phenotype embryo cell experimental study genome wide association study genomic locus high risk induced pluripotent stem cell innovation insertion/deletion mutation neurotransmission new therapeutic target pharmacologic promoter repaired risk variant stem cells therapeutic target

项目摘要

PROJECT SUMMARY Until now, CRISPR has not been readily applied to isolate linked genome-wide association studies (GWAS) alleles as Cas9 tends to re-cut the donor template. Our project will be the first to establish that CRISPR-edited cells can be used to isolate closely linked alleles in a GWAS-associated disease. Furthermore, research on age-related conditions uses traditional cultured cells as the metabolic backdrop for studies. Given that these rapidly proliferating cells more closely resemble embryonic cells than aged adult cells, they likely do not provide the appropriate environment to study the molecular biology of aging. Here, we propose to use cells that have been pharmacologically aged, enabling our model to better recapitulate the conditions present in the older adult eye, and ultimately identify appropriate areas of intervention. By using this innovative approach, we will develop a patient-specific disease model to test not only the particular mutations addressed in this application, but also other mutations and, potentially, other age-related retinal diseases down the road.

项目摘要到目前为止，CRISPR尚未轻易应用于隔离链接的全基因组关联研究（GWAS）等位基因 CAS9倾向于重新切割供体模板。我们的项目将是第一个确定CRISPR编辑的细胞可以是用于分离与GWAS相关疾病紧密连接的等位基因。此外，对年龄有关的研究条件使用传统的培养细胞作为研究代谢背景。鉴于这些快速增殖的细胞与老年成年细胞相比，它们与胚胎细胞更相似，它们可能不提供适当的环境研究衰老的分子生物学。在这里，我们建议使用已经老化的细胞，使得我们的模型更好地概括了老年人眼中存在的状况，并最终确定干涉。通过使用这种创新的方法，我们将开发一个特异性疾病模型，不仅测试本应用程序中涉及的特定突变，以及其他突变，可能是其他与年龄有关的视网膜疾病在路上。