Telomeric dysfunction and the premature aging and cancer-prone disease Werner syn

端粒功能障碍与过早衰老和癌症易发疾病 Werner Syn

• 批准号: 7886766
• 负责人: DAVID KEITH ORREN
• 金额: $ 23.79万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7886766
• 关键词: Affect; Age; Aging; Apoptosis; Apoptotic; Atherosclerosis; Back; Binding; Biochemical; Cataract; Cell Aging; Cell Death; Cell division; Cells; Characteristics; Chromosomal Instability; Chromosomes; Chronic; Cisplatin; DNA; DNA Damage; DNA Structure; DNA lesion; Development; Diabetes Mellitus; Disease; Dose; Ensure; Enzymes; Exonuclease; Fibroblasts; Frequencies; Functional disorder; Genes; Genetic Recombination; Genome; Genome Stability; Hereditary Disease; Human; Hypertension; Individual; Investigation; Kinetics; Knowledge; Laboratories; Length; Life; Link; Maintenance; Malignant Neoplasms; Mediating; Metabolic; Metabolism; Methods; Modeling; Monitor; Normal Cell; Osteoporosis; Oxidative Stress; Pathway interactions; Patients; Phenotype; Play; Premature aging syndrome; Process; Proteins; Reaction; Research; Resolution; Role; Solid; Structure; Study models; TERF1 gene; Telomerase; Telomere Maintenance; Telomeric Repeat Binding Protein 2; Time; Tissues; Werner Syndrome; Work; age related; early onset; helicase; human WRN protein; loss of function; normal aging; nuclease; premature; prevent; public health relevance; research study; senescence; telomere; tumor progression

DESCRIPTION (provided by applicant): Telomeres are specialized structures on chromosome ends that are essential for genome stability and cellular replicative capacity. Maintenance of proper telomere structure and length allows continued cell division. However, most replicating cells in the body do not express the maintenance enzyme telomerase and gradually lose telomeric DNA, eventually reaching a critically short telomere length that triggers cellular senescence and/or apoptosis. Theoretically, significant accumulation of senescent cells or loss of apoptotic cells in tissues occurs late in life and may underlie development of certain normal aging characteristics. However, solid support for the relationship between telomere dysfunction, cellular senescence and possible aging phenotypes in normal individuals is currently lacking. The premature aging disease Werner syndrome (WS) that shows early onset and increased frequency of many deleterious aging features (including cancer, atherosclerosis, osteoporosis, cataracts, diabetes, and hypertension) is caused by loss of function of a single protein, WRN. Cells derived from WS patients show telomeric abnormalities and a dramatic premature cellular senescence that is prevented by prior expression of telomerase. Investigations from several laboratories (including ours) indicate that WRN functions in telomere maintenance, possibly in coordination with the telomeric protein TRF2. Thus, WS is an excellent model for studying the relationships between telomere maintenance, cellular senescence, apoptosis, and development of specific aging characteristics. This proposal will examine the biochemical activities of WRN (in conjunction with TRF2 and other telomeric factors) on relevant telomeric DNA structures and determine its protein partners during its function in telomere metabolism with specific emphasis on telomeric replication. In addition, telomere dynamics (replication kinetics and length alterations) and cellular senescence in normal and WS cells will be examined during chronic treatment with selected DNA damaging agents. These studies will clarify the telomeric function of WRN and determine whether persistent DNA lesions in telomeric regions exacerbate telomere loss over time in WS cells compared to normal cells, and provide further support to the role of telomere dysfunction in the development of specific age-related characteristics in WS as well as in normal aging. Thus, this proposal will implicate and examine basic mechanisms at work in genome maintenance and suppression of certain aging phenotypes as well as cancer. PUBLIC HEALTH RELEVANCE: This proposal examines the role of a specific protein, WRN, in the maintenance of chromosome ends, otherwise known as telomeres. When the function of human WRN is lost (in the hereditary disease Werner syndrome), the resulting telomeric abnormalities trigger cell senescence or cell death and, in time, cause early development of aging features and cancer in affected individuals. By investigating Werner syndrome and the role of WRN in telomere metabolism, this proposal will help understand basic cellular mechanisms that act to suppress development of specific aging characteristics as well as cancer.

描述（由申请人提供）：端粒是染色体末端的特殊结构，对于基因组稳定性和细胞复制能力至关重要。维持适当的端粒结构和长度可以使细胞持续分裂。然而，体内大多数复制细胞不表达端粒酶维持酶，并逐渐失去端粒DNA，最终达到极短的端粒长度，从而引发细胞衰老和/或凋亡。理论上，组织中衰老细胞的显着积累或凋亡细胞的损失发生在生命后期，并且可能是某些正常衰老特征发展的基础。然而，目前对于正常个体中端粒功能障碍、细胞衰老和可能的衰老表型之间的关系缺乏坚实的支持。早衰疾病沃纳综合征 (WS) 是由单一蛋白质 WRN 功能丧失引起的，该疾病表现出许多有害衰老特征（包括癌症、动脉粥样硬化、骨质疏松症、白内障、糖尿病和高血压）的早发性和频率增加。来自 WS 患者的细胞表现出端粒异常和显着的细胞过早衰老，而端粒酶的先前表达可以防止这种情况。多个实验室（包括我们实验室）的调查表明，WRN 在端粒维持中发挥作用，可能与端粒蛋白 TRF2 协同作用。因此，WS 是研究端粒维持、细胞衰老、细胞凋亡和特定衰老特征发展之间关系的优秀模型。该提案将检查 WRN（与 TRF2 和其他端粒因子结合）对相关端粒 DNA 结构的生化活性，并确定其在端粒代谢功能期间的蛋白质伙伴，特别强调端粒复制。此外，在使用选定的 DNA 损伤剂进行长期治疗期间，将检查正常细胞和 WS 细胞的端粒动力学（复制动力学和长度变化）和细胞衰老。这些研究将阐明 WRN 的端粒功能，并确定与正常细胞相比，端粒区域持续性 DNA 损伤是否会随着时间的推移加剧 WS 细胞的端粒丢失，并为端粒功能障碍在 WS 特定年龄相关特征的发展以及正常衰老中的作用提供进一步支持。因此，该提案将涉及并检查基因组维持和抑制某些衰老表型以及癌症的基本机制。公共健康相关性：该提案研究了特定蛋白质 WRN 在维持染色体末端（也称为端粒）中的作用。当人类 WRN 功能丧失时（在遗传性疾病维尔纳综合征中），由此产生的端粒异常会引发细胞衰老或死亡，并最终导致受影响个体早期出现衰老特征和癌症。通过研究维尔纳综合征和 WRN 在端粒代谢中的作用，该提案将有助于了解抑制特定衰老特征以及癌症发展的基本细胞机制。