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: 7527641
• 负责人: DAVID KEITH ORREN
• 金额: $ 24.03万
• 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/7527641
• 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; Condition; DNA; DNA Damage; DNA Structure; DNA lesion; Development; Diabetes Mellitus; Disease; Disease regression; 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; Public Health; Reaction; Research; Resolution; Role; Solid; Structure; Study models; TERF1 gene; Telomerase; Telomere Maintenance; Telomeric Repeat Binding Protein 2; Time; Tissues; WRN gene; Werner Syndrome; Work; age related; early onset; helicase; human WRN protein; loss of function; normal aging; nuclease; prevent; 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专门结构，这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持续的细胞分裂。然而，体内大多数复制细胞不会表达维持酶端粒酶并逐渐失去端粒DNA，最终达到了近距离短的端粒长度，从而触发细胞衰老和/或凋亡。从理论上讲，衰老细胞的显着积累或组织中凋亡细胞的丧失发生在生命后期，可能是某些正常衰老特征的发展。但是，目前缺乏对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关系的坚实支持。早熟疾病Werner综合征（WS）显示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）的频率增加，这是由单个蛋白质，WRN的功能丧失引起的。源自WS患者的细胞表现出端粒异常，并且通过先前表达端粒酶预防的急剧过早细胞衰老。来自几个实验室（包括我们的）的研究表明，WRN在端粒维持中的功能可能与端粒蛋白TRF2协调。因此，WS是研究端粒维持，细胞衰老，凋亡和特定衰老特征发展之间关系的绝佳模型。该建议将检查WRN的生化活性（与TRF2和其他端粒因子结合使用）对相关的端粒DNA结构，并在其在端粒代谢中的功能中确定其蛋白质伴侣，并确定对端粒复制的特定强调。此外，在慢性治疗选定的DNA损伤剂治疗期间，将检查端粒动力学（复制动力学和长度改变）和正常细胞中的细胞衰老。这些研究将阐明WRN的端粒功能，并确定与正常细胞相比，端粒区域的持续性DNA病变会加剧端粒的端粒损失，并在WS以及正常衰老中的特定年龄相关特性中的发展提供进一步的支持。因此，该提案将在基因组维持和抑制某些衰老表型和癌症的抑制中牵涉并检查基本机制。公共卫生相关性：该提案研究了特定蛋白质WRN在维持染色体末端的作用，否则称为端粒。当人WRN的功能丢失（在遗传性疾病Werner综合征中）时，由此产生的端粒异常会触发细胞衰老或细胞死亡，并且随着时间的推移会导致受影响个体的衰老特征和癌症的早期发展。通过研究Werner综合征和WRN在端粒代谢中的作用，该建议将有助于理解抑制特定衰老特征和癌症发展的基本细胞机制。