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Dysfunctional Telomeres, Checkpoints and Aging

功能失调的端粒、检查点和衰老

基本信息

批准号：
7484951
负责人：
Kwok Kin Wong
金额：
$ 27.08万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-30 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7484951
关键词：
ATM activation Acceleration Age Aging Aging-Related Process Alleles Apoptosis Autopsy Biological Biological Models Breeding Cell Aging Cell Death Cell division Cells Chickens Chromosomal Rearrangement Chromosomes Complex Cultured Cells DNA Data Doctor of Medicine Doctor of Philosophy Engineering Event Failure Functional disorder Gene Dosage Generations Genes Genetic Genome Genome Stability Genomic Instability Genotype Histocompatibility Testing Homeostasis In Vitro Incidence Length Light Link Longevity Malignant Neoplasms Modeling Molecular Molecular Cytogenetics Molecular Genetics Mus Mutant Strains Mice Mutation Numbers Organ Organ failure Oxidative Stress Pathologic Pathway interactions Phenotype Physiological Play Population Premature aging syndrome Prevention Process Range Rate Reading Reserve Stem Cell Role Series Signal Transduction Staging Stem cells Structure TP53 gene Tamoxifen Telomerase Telomere Maintenance Telomere Shortening Testing Therapeutic Intervention Time Tissues Tumor Suppression Upper arm Work animal tissue base beta Actin body system cancer genome carcinogenesis cell type cellular targeting cohort exhaust in vivo insight mouse model mutant mutant mouse model prevent reconstitution response senescence stem telomere tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Telomeres are specialized capping structures on chromosomes that play important roles in aging, cancer and genome stability. With each cell division, telomeres progressively shorten such that upon reaching a critical stage, they signal cells to stop dividing. This process likely prevents cells from acquiring mutations that may result in cancer or aging. When mutations occur in crucial genes that regulate telomere maintenance or checkpoint responses (such as p53 and ATM), telomeres become critically shortened and dysfunctional. Our recent findings linking telomere dysfunction to precursor/stem cell depletion and accelerated aging in the combined telomerase Atm mutant mouse model provide a unique opportunity and genetic platform to explore the molecular mechanisms by which telomere dysfunction contributes to aging, organ homeostasis and tumorigenesis. We hypothesize that mice engineered to have critically short telomeres and defective checkpoint responses due to mTerc and Atm deficiency will be predisposed to either accelerated aging or tumorigenesis depending on p53 status. We also believe that reconstitution of telomerase activity in different organ compartments of these mice will, depending on the state of the genome at the time of the reconstitution, either strongly promote organ specific tumor progression or rescue the organ stem/progenitor cell depletion phenotype as well as suppressing tumorigenesis. Lastly, detailed molecular characterization of pathways leading to activation of p53 function in primary cells and tissues from these compound mutant mice with accelerated aging and precursor/stem cell depletion will dissect the molecular pathways that are involved in the process of aging and organ homeostasis.

描述（由申请人提供）：端粒是染色体上的专门的加帽结构，在衰老、癌症和基因组稳定性中起重要作用。随着每次细胞分裂，端粒逐渐缩短，当达到关键阶段时，它们会发出信号让细胞停止分裂。这个过程可能会阻止细胞获得可能导致癌症或衰老的突变。当调节端粒维持或检查点反应的关键基因（如p53和ATM）发生突变时，端粒会严重缩短并功能失调。我们最近的研究结果将端粒功能障碍与前体/干细胞耗竭和联合端粒酶Atm突变小鼠模型中的加速衰老联系起来，这为探索端粒功能障碍导致衰老、器官稳态和肿瘤发生的分子机制提供了独特的机会和遗传平台。我们假设，由于mTerc和Atm缺陷而被设计为具有严重短端粒和缺陷检查点反应的小鼠将倾向于加速衰老或肿瘤发生，这取决于p53状态。我们还相信，根据重建时基因组的状态，这些小鼠不同器官区室中端粒酶活性的重建将强烈促进器官特异性肿瘤进展或拯救器官干/祖细胞耗竭表型以及抑制肿瘤发生。最后，详细的分子表征的途径，导致激活p53功能的原代细胞和组织从这些化合物突变小鼠加速老化和前体/干细胞耗竭将解剖的分子途径，参与衰老和器官稳态的过程。