Telomerase in Development, Senescence and Neoplasia

端粒酶在发育、衰老和肿瘤中的作用

基本信息

批准号：
7195083
负责人：
RONALD ANTHONY DEPINHO
金额：
$ 57.41万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-01-01 至 2009-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7195083
关键词：
Address Aging-Related Process Alleles Animals Apoptotic Applied Genetics Ataxia Telangiectasia Attenuated Benign Biochemical Biological Biological Preservation Bloom Syndrome Candidate Disease Gene Categories Cell Line Cells Chimeric Proteins Chronic Cirrhosis Colonoscopy Colorectal Cancer Complementary DNA Complex Condition DNA Damage DNA copy number Degenerative Disorder Depth Development Disease Endoscopy Engineering Epithelial Estrogen Receptors Event Evolution Extinction (Psychology)Foundations Functional disorder Gastrointestinal tract structure Gene Expression Profile Genes Genetic Screening Genome Genomic Instability Genomics Grant Growth Homeostasis Human Image In Situ Indium Inherited Intestines Knock-in Mouse Knock-out Knockout Mice Large Intestine Carcinoma Lesion Life Link Liver Failure Longevity Malignant - descriptor Malignant Neoplasms Modality Modeling Molecular Monitor Neoplasm Metastasis Neoplasms Nodal Normal tissue morphology Organ Pathway interactions Phase Phenotype Premature aging syndrome Production RNA RNA Interference Relative (related person)Research Personnel Reserve Stem Cell Role Series Signal Transduction Source Staging Stem cells Structure Syndrome System TP53 gene Telomerase Therapeutic Time Tissue Preservation Tissues Transactivation Werner Syndrome Work age related aged base biological adaptation to stress body system cancer risk cost functional restoration knock-down malignant state miniaturize mouse model novel programs resistance mechanism response restoration senescence sensor size telomerase reverse transcriptase telomere tissue regeneration tumor tumor growth tumor progression villin

项目摘要

DESCRIPTION (provided by applicant): The principal focus of this renewal application is to explore the complex roles of telomeres, telomerase and p53 in tumor progression and metastases. Work from the current grant has utilized telomerase knockout mice to explore the complex roles of telomeres and telomerase in normal tissue regeneration, the aging process, acquired and inherited degenerative disorders, and cancer. Analysis of this model on the molecular, cellular and organismal levels has established that intact telomeres are essential for the long-term preservation of tissue stem cells and organ function, that telomere dysfunction is a key pathogenetic element in age-related and degenerative disorders, and that p53 is a nodal point in sensing telomere dysfunction and in executing a complex array of telomere checkpoint responses across different tissue compartments. Most relevant to the renewal application, this model also established that telomere dysfunction drives cancer initiation (particularly epithelial cancers) by provoking cancer-associated chromosomal structural aberrations, particularly amplifications and deletions. While cancer initiation is increased, the current work also suggests that ongoing telomere dysfunction and associated p53-dependent telomere checkpoint operate to constrain progression of these initiated neoplasms into advanced highly malignant disease. Upon this foundation, we now propose to explore how the telomere and p53 pathway interact to govern the survival or depletion of tissue stem cells and ultimately their transformation and evolution into fully malignant disease. Specifically, we propose the development of a novel inducible alleles for telomerase reverse transcriptase and p53 to assess the impact of somatic restoration of telomere function on stem cell depletion brought about by telomere dysfunction, to apply genetic screens to define the molecular circuitry of the telomere checkpoint response, to explore the relative contributions of telomerase reactivation and p53 inactivation in tumor progression, and to ascertain the molecular and biological response of established tumors to extinction of telomere activity and re-entry into telomere-based crisis.

描述（由申请人提供）：此更新应用的主要重点是探索端粒，端粒酶和p53在肿瘤进展和转移酶中的复杂作用。当前赠款的工作利用端粒酶基因敲除小鼠探索端粒和端粒酶在正常组织再生中的复杂作用，衰老过程，获得和遗传的退行性疾病以及癌症。 Analysis of this model on the molecular, cellular and organismal levels has established that intact telomeres are essential for the long-term preservation of tissue stem cells and organ function, that telomere dysfunction is a key pathogenetic element in age-related and degenerative disorders, and that p53 is a nodal point in sensing telomere dysfunction and in executing a complex array of telomere checkpoint responses across different tissue车厢。该模型与续签应用最相关的是，该模型还确定，端粒功能障碍通过引起与癌症相关的染色体结构畸变（尤其是放大和缺失）来促进癌症开始（尤其是上皮癌）。尽管癌症的开始增加了，但目前的工作还表明，持续的端粒功能障碍和相关的p53依赖性端粒检查点可将这些引发肿瘤的进展限制为高级高度恶性疾病。在这个基础上，我们现在建议探索端粒和p53途径如何相互作用以控制组织干细胞的存活或耗尽，并最终转化和进化为完全恶性疾病。 Specifically, we propose the development of a novel inducible alleles for telomerase reverse transcriptase and p53 to assess the impact of somatic restoration of telomere function on stem cell depletion brought about by telomere dysfunction, to apply genetic screens to define the molecular circuitry of the telomere checkpoint response, to explore the relative contributions of telomerase reactivation and p53 inactivation in tumor progression, and确定已建立肿瘤对端粒活性灭绝并重新进入基于端粒的危机的分子和生物学反应。