A Human Model for Telomerase Dysfunction and Aging

端粒酶功能障碍和衰老的人体模型

• 批准号: 7391533
• 负责人: ALOYSIUS John KLINGELHUTZ
• 金额: $ 27.06万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7391533
• 关键词: Affect; Age; Aging; Alopecia; Biological Assay; Biological Models; Biology; Biology of Aging; Cell physiology; Cells; Chronic; DNA Damage; Data; Defect; Development; Disease; Down-Regulation; Dyskeratosis Congenita; Elderly; Enzymes; Epidermis; Fibroblasts; Functional disorder; Genes; Goals; Human; Hypopigmentation; In Vitro; Inherited; Length; Leukoplakia; Link; Methods; Modeling; Mutation; Normal Cell; Normal tissue morphology; Organ; Oxidative Stress; Pancytopenia; Pathway interactions; Patients; Phenotype; Play; Premature aging syndrome; Process; Proliferating; Pulmonary Fibrosis; RNA; RNA-Directed DNA Polymerase; Rate; Relative (related person); Research Personnel; Role; Skin; Skin Aging; Somatic Cell; Stress; Telomerase; Telomerase RNA Component; Telomere Maintenance; Telomere Shortening; Testing; Tissues; Toxic effect; Wound Healing; age effect; aged; base; biological adaptation to stress; cancer cell; cancer therapy; cell type; follow-up; insight; keratinocyte; mutant; normal aging; novel; novel strategies; programs; reconstitution; research study; response; restoration; small hairpin RNA; telomere; vector

DESCRIPTION (provided by applicant): Telomere shortening, a natural consequence of aging, and telomerase dysfunction have recently been linked with certain diseases associated with defects in highly proliferative tissue, including the epidermis. Our long-term goal is to understand the contribution of telomerase and telomere length in regulating the function and aging of human skin. Dyskeratosis congenita (DC) is an inherited "premature aging" syndrome characterized by epidermal abnormalities (e.g. leukoplakia, skin hypopigmentation, alopecia) and organ dysfunction (e.g. bone marrow failure, pulmonary fibrosis). DC is caused by mutations in genes that affect telomerase activity, resulting in shortening of telomeres in somatic cells. We recently identified an autosomal dominant form of this disease (AD DC) that is due to a deletion in hTERC, the RNA component of telomerase. AD DC provides a unique human model system to study the regulatory role of telomerase and telomere shortening in the biology of aging. We propose that telomerase and telomere length are important regulators of normal keratinocyte function, differentiation, and response to stress. Furthermore, we hypothesize that skin aging is associated with telomere length shortening and dysregulation of telomerase component expression. Using skin keratinocytes and fibroblasts isolated from AD DC subjects, normal controls and experimentally manipulated cells, we will further define the role of telomerase and telomere length in regulating DNA damage and oxidative stress response pathways. We will determine whether introduction of telomerase components, hTERC and/or hTERT, into AD DC cells restores replicative potential, cellular function, and normal responses to stress and DNA damage. We will also explore the possibility that hTERT has functions in keratinocytes that go beyond telomere maintenance and perform studies to determine whether the unusually long telomeres associated co-expression of hTERC and hTERT have any effects on cell phenotype. Overall, the experiments proposed in this application will further our understanding of the role of telomerase and telomeres in cellular defects associated with aging, and provide critical mechanistic insights into the processes that govern normal skin function and aging. Importantly, these findings may also promote the development of novel strategies aimed at reducing the effects of aging on human skin and other tissues, and in ameliorating the toxicity of cancer therapies in the elderly.

描述（由申请人提供）：端粒缩短，衰老的自然结果以及端粒酶功能障碍最近与某些与高度增殖组织（包括表皮）中的缺陷相关的疾病有关。我们的长期目标是了解端粒酶和端粒长度在调节人皮肤功能和衰老方面的贡献。康格诺塔（DC）是一种遗传性的“过早衰老”综合征，其特征是表皮异常（例如白细胞，皮肤不形成，脱落）和器官功能障碍（例如，骨髓失败，肺纤维化）。 DC是由影响端粒酶活性的基因突变引起的，导致体细胞中端粒的缩短。我们最近确定了这种疾病的常染色体显性形式（AD DC），该形式是由于端粒酶RNA成分HTERC的缺失所致。 AD DC提供了一个独特的人类模型系统，以研究端粒酶和端粒缩短在衰老生物学中的调节作用。我们建议端粒酶和端粒长度是正常角质形成功能，分化和对压力的反应的重要调节剂。此外，我们假设皮肤衰老与端粒长度缩短和端粒酶成分表达的失调有关。使用从AD DC受试者，正常对照和实验操纵细胞中分离出的皮肤角质形成细胞和成纤维细胞，我们将进一步定义端粒酶和端粒长度在调节DNA损伤和氧化应激反应途径中的作用。我们将确定将端粒酶成分（HTERC和/或HTERT）引入AD DC细胞中是否会恢复复制潜力，细胞功能以及对应激和DNA损伤的正常响应。我们还将探讨HTERT在角质形成细胞中具有功能的可能性，这些可能性超出了端粒维持并进行研究以确定与HTERC和HTERT相关的异常长端粒是否对细胞表型有任何影响。总体而言，本应用程序中提出的实验将进一步了解端粒酶和端粒在与衰老相关的细胞缺陷中的作用，并为控制正常皮肤功能和衰老的过程提供关键的机械洞察力。重要的是，这些发现还可能促进旨在减少衰老对人皮肤和其他组织的影响的新型策略的发展，并改善老年人癌症疗法的毒性。