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

• 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
• 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

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还没有被容易地应用于分离连锁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 用于分离GWAS相关疾病中紧密连锁的等位基因。此外，与年龄有关的研究 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，它们更像胚胎细胞，它们可能无法提供合适的环境， 研究衰老的分子生物学。在这里，我们建议使用已被封装的细胞， 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。 干预通过使用这种创新方法，我们将开发一种患者特异性疾病模型，不仅可以测试 本申请中所述的特定突变，但也包括其他突变，以及潜在的其他年龄相关的视网膜病变。 疾病在路上