Senescence and Longevity Modulating Genes, WRN and BLM

衰老和长寿调节基因、WRN 和 BLM

基本信息

批准号：
7260443
负责人：
Judith Campisi
金额：
$ 23.47万
依托单位：
UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB
依托单位国家：
美国
项目类别：
财政年份：
1993
资助国家：
美国
起止时间：
1993-09-06 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7260443
关键词：
Adult Aging Apoptosis Apoptotic Appearance Atherosclerosis Behavior Bloom Syndrome Bloom syndrome protein Cancer Etiology Cardiovascular Diseases Cataract Cell Aging Cell Survival Cell physiology Cells Cessation of life DNA Damage DNA Double Strand Break DNA Repair Development Disease Double Strand Break Repair Employee Strikes Erythema Family Genome Genomic Instability Genomics Goals Growth Human In Vitro Individual Lesion Life Longevity Maintenance Male Infertility Malignant Neoplasms Mammals Modeling Mus Mutation Non-Insulin-Dependent Diabetes Mellitus Nonhomologous DNA End Joining Normal Cell Osteoporosis Outcome Pathology Pathology, Other Phenotype Process Progeria Protein Kinase Proteins Role Signaling Protein Substrate Specificity Syndrome System Telomere Maintenance Tumor Suppressor Proteins WRN gene Werner Syndrome age related aged base early onset helicase human WRN protein insight member mutant prevent protein function recombinational repair repaired response senescence telomere tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Genomic maintenance systems are important determinants of longevity in all species. In mammals, DNA damage and faulty repair are major causes of cancer and non-cancer aging phenotypes. Normal cells respond to unrepaired DNA damage by apoptosis or cellular senescence, which suppress tumorigenesis but may also contribute to age-related pathology. WRN and BLM are related members of the mammalian RECQ-like family of DNA helicases. Current evidence suggests that both proteins participate in repairing DNA damage, among other possible functions. The phenotypes of humans deficient in these helicases suggest that both proteins prevent certain age-related diseases, including cancer. Werner syndrome (WS) and Bloom syndrome (BS) are caused by a deficiency in WRN and BLM, respectively. WS and BS share several features, but also show striking differences, the bases for which are largely unknown. Our overall goal is to better understand the cellular functions of the human WRN and BLM proteins. We propose to focus primarily on human cells, and determine how WRN and BLM are regulated, and how they regulate responses to DNA damage. We propose to determine effects of wild type and mutant WRN and BLM proteins on the senescence and apoptotic responses, telomere dynamics and genomic integrity of human cells. We will also determine how selected damage-sensing protein kinases regulate the subnuclear localization of WRN and BLM and its response to DNA damage. Our studies will provide important insights into how WRN and BLM postpone the development of aging phenotypes and the development of cancer in humans.

描述（由申请人提供）：基因组维护系统是所有物种寿命的重要决定因素。在哺乳动物中，DNA损伤和修复错误是癌症和非癌症衰老表型的主要原因。正常细胞通过细胞凋亡或细胞衰老对未修复的DNA损伤做出反应，这抑制了肿瘤发生，但也可能导致与年龄相关的病理。 WRN和BLM是哺乳动物RECQ样DNA解旋酶家族的相关成员。当前的证据表明，两种蛋白质都参与修复DNA损伤，以及其他可能的功能。这些解旋酶缺乏人类的表型表明，两种蛋白质都可以预防某些与年龄有关的疾病，包括癌症。 Werner综合征（WS）和Bloom综合征（BS）分别由WRN和BLM缺乏引起。 WS和BS具有多个功能，但也显示出惊人的差异，其基础在很大程度上未知。我们的总体目标是更好地了解人WRN和BLM蛋白的细胞功能。我们建议主要关注人类细胞，并确定如何调节WRN和BLM，以及它们如何调节对DNA损伤的反应。我们建议确定野生型和突变体WRN和BLM蛋白对人类细胞的衰老和凋亡反应，端粒动力学以及基因组完整性的影响。我们还将确定选定的损伤蛋白激酶如何调节WRN和BLM的亚核定位及其对DNA损伤的反应。我们的研究将为WRN和BLM推迟衰老表型的发展以及人类癌症的发展如何提供重要的见解。