Assessing therapeutic intervention of short telomere syndromes

评估短端粒综合征的治疗干预

基本信息

批准号：
10469230
负责人：
Yie Liu
金额：
$ 88.86万
依托单位：
NATIONAL INSTITUTE ON AGING
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10469230
关键词：
Acetylation Affect Aging Animal Model Bioavailable Biochemical Reaction Biological Biological Aging Biological Availability Cell Aging Cell physiology Consumption DNA Damage DNA Repair Disease Disease model Dyskeratosis Congenita Energy Metabolism Enzymes Fibroblasts Functional disorder Generations Genes Genome Germ-Line Mutation Health Homeostasis Impairment Inherited Intervention Knock-out Length Link Maintenance Mediating Metabolism Mitochondria Molecular Mus Nicotinamide adenine dinucleotide Oxidation-Reduction Pancytopenia Pathway interactions Patients Pharmacological Treatment Phenotype Premature aging syndrome RNA-Directed DNA Polymerase Reaction SIRT1 gene Signal Transduction Sirtuins Supplementation Syndrome TP53 gene Telomerase Telomere Maintenance Therapeutic Intervention age related aged healthspan improved in vivo insight metabolome mouse model nicotinamide riboside supplementation nicotinamide-beta-riboside response telomere telomere loss therapeutic development treatment strategy

项目摘要

We have utilized the DC disease model as well as late generation telomerase reverse transcriptase knockout (Tert-/-) mice to investigate the relationship between short telomeres/telomere dysfunction and the NAD metabolome. Our studies revealed several insights: (i) primary fibroblasts derived from DC patients and late generation Tert-/- mice with short telomere lengths have lower NAD levels and display an imbalance in the NAD metabolome that includes elevated CD38, and reduced PARP1 and SIRT1 expression and activities; (ii) DC fibroblasts are defective in the NAD-consuming enzyme-related signaling networks, including the NAD-SIRT1-PGC-1-mitochondria and the NAD-PARP-telomere DNA repair axis; and (iii) NR supplementation and CD38 inhibition restore NAD levels and/or NAD-consuming PARP and SIRT activities, alleviate p53 acetylation, telomere DNA damage, mitochondrial impairment including cellular and mitochondrial ROS, and mostly importantly, delay the onset of replicative senescence in DC fibroblasts. Our results support the idea that telomere loss/dysfunction interferes with the NAD metabolism and related biological pathways, thereby contributing to telomere and mitochondrial abnormalities and cellular senescence. Our studies pave the way for the development of therapeutic strategies for the treatment of short telomere syndromes as well as age-related disorders. We will continue to explore the following questions: a) The molecular pathways linking telomere dysfunction and CD38 hyperactivation, b) Is CD38 hyperactivation responsible for telomere loss/dysfunction-mediated pathophysiology in vivo, and c) Does re-equilibration of imbalanced NAD metabolism ameliorates telomere loss/dysfunction-mediated pathophysiology in vivo.

我们利用了DC疾病模型以及后期端粒酶逆转录酶敲除（TERT - / - ）小鼠来研究短端粒/端粒功能障碍与NAD代谢组之间的关系。我们的研究揭示了几种见解：（i）源自直流患者的原发性成纤维细胞和短端粒长度的晚期TERT - / - 小鼠的NAD水平较低，并且在NAD代谢组中表现出不平衡，包括升高的CD38，以及降低PARP1和SIRT1的表达和活动；（ii）DC成纤维细胞在与NAD酶相关的信号网络中有缺陷，包括NAD-SIRT1-PGC-1-MINOCHOCHIAS和NAD-PARP-TELOMERE DNA RESTION AXIS； and (iii) NR supplementation and CD38 inhibition restore NAD levels and/or NAD-consuming PARP and SIRT activities, alleviate p53 acetylation, telomere DNA damage, mitochondrial impairment including cellular and mitochondrial ROS, and mostly importantly, delay the onset of replicative senescence in DC fibroblasts.我们的结果支持端粒损失/功能障碍会干扰NAD代谢和相关的生物学途径，从而导致端粒和线粒体异常和细胞衰老。我们的研究为制定治疗短端粒综合征和与年龄有关的疾病的治疗策略的发展铺平了道路。 We will continue to explore the following questions: a) The molecular pathways linking telomere dysfunction and CD38 hyperactivation, b) Is CD38 hyperactivation responsible for telomere loss/dysfunction-mediated pathophysiology in vivo, and c) Does re-equilibration of imbalanced NAD metabolism ameliorates telomere loss/dysfunction-mediated pathophysiology in体内。