Identifying mechanisms that detect and eliminate aneuploid cells

识别检测和消除非整倍体细胞的机制

• 批准号: 10320458
• 负责人: Nicholas E Baker
• 金额: $ 24.03万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10320458
• 关键词: Abnormal Cell; Acids; Affect; Age related macular degeneration; Aging; Aneuploid Cells; Aneuploidy; Apoptosis; Biogenesis; Blindness; Cataract; Cell physiology; Cells; Chemicals; Chromosome 2; Chromosome 3; Chromosome Arm; Chromosome abnormality; Chromosomes; Data; Defect; Development; Diploidy; Disease; Disease Progression; Dose; Drosophila genus; Elderly; Epithelial; Ethane; Excision; Eye; Eye diseases; Gene Mutation; Gene Proteins; Genes; Genetic Screening; Genome Mappings; Glaucoma; Goals; Incidence; Maps; Mediating; Methods; Mitotic Recombination; Molecular; Mutation; Normal Cell; Point Mutation; Population; Process; Proxy; Research; Retinal Ganglion Cells; Ribosomal Proteins; Ribosomes; Structure of retinal pigment epithelium; Study models; Tissues; Vision; age related; base; fly; genome sequencing; insight; lens; mouse model; mutant; mutation screening; novel; prevent; senescence; whole genome

Age-related macular degeneration, glaucoma and cataract are major causes of vision loss and all three diseases are age-related. Each is associated with the accumulation of senescent cells in, respectively, the retinal pigmented epithelium, the retinal ganglion cells, and the lens epithelium, and mouse model studies indicate that senescent cells contribute to the occurrence and progression of these eye diseases. Senescent cells are abnormal cells that accumulate during aging, fail to divide and instead have disruptive effects on tissue function. Recent research indicates that senescent cells are aneuploid ie have chromosomal abnormalities. Aneuploid cells can be removed from developing tissues and preliminary data indicates that other cells recognize them based on imbalanced ribosomal protein gene dose. Genetic screens will be performed in fruitfly eyes to isolate gene mutations that act in normal cells to prevent their recognizing and eliminating aneuploid cells. Whole genome sequencing and mapping methods will be used to identify the genes affected by these mutations, which will provide insight into the molecular mechanisms of aneuploid cell recognition and removal. It is anticipated that these studies can help understand how senescent cells accumulate to cause age-related macular degeneration, glaucoma and cataract, and suggest approaches to reduce the incidence and progression of these eye disases.

年龄相关性黄斑变性、青光眼和白内障是视力下降的主要原因 损失和所有三种疾病都与年龄有关。每一个都与积累相关 视网膜色素上皮、视网膜中的衰老细胞分别 神经节细胞、晶状体上皮和小鼠模型研究表明 衰老细胞导致这些眼部疾病的发生和进展。 衰老细胞是在衰老过程中积累、无法分裂和分裂的异常细胞。 相反会对组织功能产生破坏性影响。最近的研究表明 衰老细胞是非整倍体，即具有染色体异常。非整倍体细胞 可以从发育中的组织中去除，初步数据表明其他 细胞根据不平衡的核糖体蛋白基因剂量来识别它们。遗传 将在果蝇眼睛中进行筛选，以分离出作用于果蝇眼睛的基因突变。 正常细胞阻止其识别和消除非整倍体细胞。所有的 基因组测序和作图方法将用于识别基因 受这些突变的影响，这将有助于深入了解分子 非整倍体细胞识别和去除的机制。预计这些 研究可以帮助了解衰老细胞如何积累导致与年龄相关的 黄斑变性、青光眼和白内障，并提出减少黄斑变性、青光眼和白内障的方法 这些眼病的发生率和进展。