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：
10576542
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/10576542
关键词：
10q Address Adult Affect Age related macular degeneration Alleles Anti-Inflammatory Agents Antioxidants Area Biology of Aging Cell Line Cells Choroid Chromosomes Clustered Regularly Interspaced Short Palindromic Repeats Coculture Techniques Complement Factor H Cultured Cells Disease Disease model Elderly Environment Etiology Eye Foundations GTP-Binding Protein alpha Subunits, Gs 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 Pharmacology Predisposition Proliferating Recording of previous events Research Retina Retinal Diseases Risk Risk Factors SOD2 gene Serine Signal Transduction Single Nucleotide Polymorphism Structure of retinal pigment epithelium Testing Thrombospondin 1 Transcript Transforming Growth Factor beta Variant age related aged blastomere structure cell age disease phenotype experimental study genome wide association study genomic locus high risk induced pluripotent stem cell innovation insertion/deletion mutation new therapeutic target 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.

项目概要到目前为止，CRISPR 尚未轻易应用于分离连锁的全基因组关联研究 (GWAS) 等位基因，因为 Cas9倾向于重新切割供体模板。我们的项目将是第一个证明 CRISPR 编辑的细胞可以用于分离 GWAS 相关疾病中密切相关的等位基因。此外，与年龄相关的研究条件使用传统的培养细胞作为研究的代谢背景。鉴于这些快速增殖的细胞与衰老的成体细胞相比，它们更类似于胚胎细胞，它们可能无法提供适当的环境研究衰老的分子生物学。在这里，我们建议使用经过药理学老化的细胞，从而能够我们的模型可以更好地概括老年人眼睛的状况，并最终确定适当的区域干涉。通过使用这种创新方法，我们将开发一种针对患者的疾病模型，不仅可以测试本申请中涉及的特定突变，还有其他突变，以及可能的其他与年龄相关的视网膜突变疾病在路上。