Cell Competition in Development and Homeostasis

发育和稳态中的细胞竞争

• 批准号: 10389459
• 负责人: Nicholas E Baker
• 金额: $ 3.61万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-20 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10389459
• 关键词: Adverse effects; Affect; Aging; Aneuploid Cells; Aneuploidy; Apoptosis; Award; Cell Nucleus; Cell Survival; Cell physiology; Cells; Chromosomes; Congenital Abnormality; Development; Disease; Dose; Drosophila genus; Female; Gene Dosage; Gene Proteins; Generations; Genes; Genetic; Genetic Recombination; Genome; Genotype; Germ Cells; Goals; Gonadal structure; Health; Homeostasis; Lead; Maintenance; Malignant Neoplasms; Measures; Methods; Modification; Mosaicism; Mutate; Mutation; Normal Cell; Parents; Pathway interactions; Physiological; Play; Positioning Attribute; Prevention; Process; Proteins; Radiation induced damage; Regulator Genes; Regulatory Pathway; Reproduction; Ribosomal Proteins; Ribosomes; Role; Somatic Cell; Testing; Tissues; age related; cell injury; cell type; defined contribution; design; fitness; genetic approach; healthy aging; male; novel; preservation; response; tissue mosaicism; transcription factor

Abstract Parent Award The genes that control many aspects of cellular function are contained on chromosomes in the cell nucleus. If these genes or the chromosomes that carry them become damaged, many aspects of cell function can be altered. Gene and chromosome changes can cause birth defects, accumulate during aging, are found in nearly every cancer, and are thought to have many adverse effects on health. This proposal hypothesizes that a set of 80 genes, dispersed around the various chromosomes, are exploited to recognize cells with large-scale genetic changes and eliminate them before they affect health. These genes encode ribosomal proteins, each one of which assembles into a unique position in the ribosome, so that ribosome assembly is affected if any are limiting. Studies in the fruitfly Drosophila document a regulatory pathway that is activated by ribosomal protein gene imbalance and that leads to cell elimination by cell competition with nearby normal cells. One goal of this proposal is to verify that ribosomal protein genes, and the regulatory genes that respond to their imbalance, are able to target cells with genetic damage for competitive elimination, and to define the range of genome damage that is subject to this regulatory mechanism in somatic tissues. A second goal is to assess the role of cell competition in protecting the germline from aneuploid genetic changes that might lead to birth defects. These studies make use of targeted genetic recombination methods using fruitfly chromosomes. These studies will establish the importance and scope of a newly-recognized mechanism that can remove cells with large- scale genetic damage, and which may play an important role in the prevention of birth defects and of cancer, as well as in healthy aging and prevention of age-related diseases.

抽象家长奖 控制细胞功能许多方面的基因包含在细胞的染色体上 原子核如果这些基因或携带它们的染色体受损， 功能可以改变。基因和染色体的变化会导致出生缺陷， 衰老，几乎在每一种癌症中都有发现，并被认为对健康有许多不利影响。这 一项提案假设，一组80个基因，分散在不同的染色体，被利用 识别具有大规模遗传变化的细胞，并在它们影响健康之前消除它们。这些 基因编码核糖体蛋白质，每一个核糖体蛋白质在核糖体中组装成一个独特的位置， 核糖体的组装会受到影响果蝇的研究 由核糖体蛋白基因失衡激活并导致细胞消除的调节途径 通过与附近正常细胞的竞争。这项提议的一个目标是验证核糖体蛋白 基因，以及对它们的不平衡做出反应的调节基因，能够靶向具有遗传学特征的细胞。 竞争性消除的损伤，并确定受此影响的基因组损伤的范围 体细胞组织中的调节机制。第二个目标是评估细胞竞争在 保护生殖系免受可能导致出生缺陷的非整倍体遗传变化的影响。这些研究 利用果蝇染色体的定向基因重组方法。这些研究将 建立一个新认识的机制的重要性和范围，可以删除细胞与大- 规模遗传损伤，并可能发挥重要作用，在预防出生缺陷和 癌症，以及健康老龄化和预防与年龄有关的疾病。