Cell Competition in Development and Homeostasis

发育和稳态中的细胞竞争

基本信息

批准号：
8421990
负责人：
Nicholas E Baker
金额：
$ 31.73万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-20 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8421990
关键词：
Accounting Address Affect Aging Aging-Related Process Amino Acid Substitution Aneuploidy Animals Apoptosis Attention Cardiovascular Diseases Cell Survival Cells Cellular Structures Code Complement Cytoplasm DNA Damage Dementia Development Diabetes Mellitus Diagnostic Neoplasm Staging Disease Drosophila genus Drosophila melanogaster Frequencies Genes Genetic Genetic Epistasis Genetic Screening Genetic Transcription Genetic Variation Genome Genomics Genotype Goals Homeostasis Individual Introns Lead Location MDM2 gene Malignant Neoplasms Mammals Modeling Molecular Mutate Mutation Neurofibromin 2 Normal Cell Nuclear Nuclear Export Pathway interactions Process Protein Binding Protein Biosynthesis Proteins RNA RNA Splicing Regulation Ribosomal Proteins Ribosomes Role Running Small Nucleolar RNA Structure Tertiary Protein Structure Testing Time Transcript Transgenes Translations Tumor Suppressor Proteins age related cell injury gene cloning in vivo mutant novel novel strategies prevent protein structure public health relevance response sensor tumor

项目摘要

DESCRIPTION (provided by applicant): The goal of this project is to elucidate mechanisms that protect the genetic integrity of individual cells. DNA damage that leads altered gene numbers in individual cells is very common in tumors, and contributes to their progression. Similar damage is thought to occur in many cells in the body over time. Indeed such damage may be a hallmark of the aging process and a contributor to age related diseases including dementia, cardiovascular disease and diabetes, in addition to cancer. By using Drosophila melanogaster mosaic animals that contain cells with differing genotypes to mimic genome alterations, the effects of such somatic genetic diversity can be studied experimentally. The project examines the hypothesis that imbalances in ribosomal protein genes can trigger a 'cell competition' response that removes them in favor or other, genetically-normal cells. The domains of particular ribosomal proteins that are responsible for this additional function, beyond the well-known role of ribosomal proteins in protein synthesis, will be established using structural and functional analysis of clones genes in vivo. Particular attention will be paid to th location within the cell where ribosomal proteins are important, and to the hypothesis that ribosomal protein imbalances activate tumor suppressors of the Salvador-Hippo-Warts pathway to promote elimination of damaged cells. Genetic screens will be conducted that will identify other components of the process, and seek to identify the molecular mechanisms whereby ribosomal protein imbalance leads to cell elimination.

描述（由申请人提供）：该项目的目的是阐明保护单个细胞遗传完整性的机制。导致单个细胞基因数改变的DNA损伤在肿瘤中非常普遍，并有助于其进展。随着时间的推移，人们认为体内许多细胞也会发生类似的损害。确实，这种损害可能是衰老过程的标志，也是与年龄相关疾病的贡献者，包括痴呆症，心血管疾病和糖尿病，除了癌症外。通过使用果蝇黑色素蛋白酶的镶嵌动物，这些动物包含具有不同基因型的细胞与模仿基因组改变的细胞，可以通过实验研究这种体细胞多样性的作用。该项目研究了以下假设：核糖体蛋白基因的失衡可以触发“细胞竞争”反应，从而消除它们有利于或其他遗传正常细胞。除了体内克隆基因的结构和功能分析，还将建立核糖体蛋白在蛋白质合成中的众所周知的作用之外，将核糖体蛋白在蛋白质合成中的众所周知的作用之外的特定核糖体蛋白的结构域。将特别注意核糖体蛋白很重要的细胞中的位置，并且假设核糖体蛋白质失衡激活了萨尔瓦多 - 河波波 - 波 - 波 - 波动途径的肿瘤抑制子，以促进消除受损细胞。将进行遗传筛选，以确定该过程的其他组成部分，并试图鉴定核糖体蛋白质失衡导致细胞消除的分子机制。