Mechanisms of longevity in the naked mole rat: high molecular weight hyaluronan and stable epigenome.

裸鼹鼠的长寿机制：高分子量透明质酸和稳定的表观基因组。

• 批准号: 10152478
• 负责人: Andrei Seluanov
• 金额: $ 31.48万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10152478
• 关键词: Acids; Address; Age; Animals; Biological Assay; Cell Culture Techniques; Cell Maintenance; Cells; Cognition; Collaborations; Contact Inhibition; Cultured Cells; Data; Data Analyses; Degenerative polyarthritis; Development; Disaccharides; Disease; Enzymes; Epigenetic Process; Excision; Extracellular Matrix; Fluorescence Polarization; Funding; Future; Gamma Rays; Genes; Genome; Genome Stability; Glycosaminoglycans; Goals; HAS2 gene; Health; Heart; Hematopoietic stem cells; Histones; Human; Hyaluronan; Hyaluronic Acid; Hyaluronidase; Intervention; Laboratories; Longevity; Malignant Neoplasms; Mediating; Metabolism; Methylation; Mole Rats; Molecular; Molecular Weight; Mus; Pathologic; Pathology; Pathway interactions; Physical Performance; Polymers; Predisposition; Production; Research; Resistance; Rodent; Role; Skin; Study models; Testing; Time; Tissues; Transgenic Mice; Translating; Tumor Suppressor Proteins; Work; age related; base; comparative genomics; design; epigenome; extracellular; fitness; healthspan; high throughput screening; histone modification; human tissue; improved; induced pluripotent stem cell; inhibitor/antagonist; metabolome; metabolomics; methylome; novel; rat genome; small molecule; small molecule inhibitor; transcriptome; transcriptomics; tumor

SUMMARY: The long-term goal of Project 2 is to understand the molecular mechanisms responsible for longevity and cancer resistance of long-lived mammalian species and then translate these strategies to humans. The naked mole rat (NMR) is the longest-lived rodent, with a maximum lifespan of 32 years. Moreover, NMRs are highly resistant to cancer and other age-related diseases. Since NMRs are related to the short-lived laboratory rodents, they represent an ideal model for studies of longevity. We identified a novel mechanism of cancer- resistance in the NMR which is mediated by abundant high molecular weight hyaluronan (HMW-HA) in naked mole rat tissues. HA is a polymer glycosaminoglycan, and a component of the extracellular matrix produced by hyaluronan synthase 2 gene (HAS2). Depleting HMW-HA from NMR cells make them prone to form tumors. In the current funding cycle, we generated transgenic mice expressing naked mole rat HAS2 (nmrHAS2 mice). Our preliminary results suggest that nmrHAS2 mice have a longer lifespan and improved fitness. These mice are resistant to osteoarthritis and have improved hematopoietic stem cell maintenance. Importantly, we found that HMW-HA levels were only modestly elevated in nmrHAS2 mice due to very high hyaluronidase (HA-degrading) activity in the mouse tissues compared to the naked mole rat. Human tissues have similarly high hyaluronidase activity. We therefore propose that downregulating hyaluronidases using small molecules is a promising strategy to increase endogenous HMW-HA levels and alleviate age-related diseases, which has translational potential. We designed a strategy for a high throughput screen for hyaluronidase inhibitors and identified the first compounds that upregulate HMW-HA levels. In search for additional mechanisms that promote NMR health and longevity, we found that NMRs have more stable epigenomes characterized by resistance to iPSC reprogramming and specific differences in histone modifications. Based on these findings, our future objectives are focused on two longevity mechanisms we identified in the NMR, namely HMW-HA and a stable epigenome. Our aims are: (1) Complete the lifespan study and characterize cancer susceptibility, tissue pathology, genome stability (with Project 3), metabolism, and methylation age (with Project 4) of nmrHAS2 mice. (2) Perform a high throughput screen for hyaluronidase inhibitors and test the effect of these compounds on health, fitness and age- related pathologies in mice. (3) Determine molecular mechanisms responsible for NMR epigenome stability. We will identify specific histone modifying enzymes that are differentially regulated in the NMR, and manipulate them to stabilize the mouse epigenome. We will collaborate with Project 1 to determine the role of SIRT6 in NMR epigenome stability, and with Project 3 to investigate genome and methylome stability in the NMR and mouse cells after epigenetic interventions. The proposed research will identify strategies for exporting the longevity mechanisms found in the naked mole rat to other species.

摘要：项目2的长期目标是了解造成长寿的分子机制 长寿哺乳动物物种的癌症耐药性，然后将这些策略转化为人类。这 裸mole大鼠（NMR）是寿命最长的啮齿动物，其寿命为32年。而且，NMR是 对癌症和其他与年龄有关的疾病具有高度抗性。由于NMR与短寿命实验室有关 啮齿动物，它们代表了研究寿命研究的理想模型。我们确定了一种新的癌症机制 NMR的抗性，该NMR由大量的高分子量透明质酸（HMW-HA）介导 摩尔大鼠组织。 HA是一种聚合物糖胺聚糖，也是由细胞外基质的成分 透明质酸合酶2基因（HAS2）。从NMR细胞中耗尽的HMW-HA使它们容易形成肿瘤。在 当前的融资周期，我们产生了表达裸mole大鼠HAS2（NMRHAS2小鼠）的转基因小鼠。我们的 初步结果表明NMRHAS2小鼠的寿命更长，并且适应性提高。这些老鼠是 对骨关节炎的抗性，并改善了造血干细胞的维持。重要的是，我们发现 由于非常高的透明质酸酶（HA降解），NMRHAS2小鼠的HMW-HA水平仅被适度升高 与赤摩尔大鼠相比，小鼠组织的活性。人体组织具有类似的透明质酸酶 活动。因此，我们建议使用小分子下调透明质酸酶是一个有前途的策略 增加内源性HMW-HA水平并减轻具有转化潜力的年龄相关疾病。 我们为透明质酸酶抑制剂设计了高通量屏幕的策略，并确定了第一个 上调HMW-HA水平的化合物。寻找促进NMR健康和的其他机制 寿命，我们发现NMR具有更稳定的表观基因组，其特征是对IPSC的抗性 在组蛋白修饰中重新编程和特定差异。基于这些发现，我们的未来目标 专注于我们在NMR中鉴定出的两种寿命机制，即HMW-HA和一个稳定的表观基因组。 我们的目的是：（1）完成寿命研究并表征癌症易感性，组织病理学，基因组 NMRHAS2小鼠的稳定性（带有项目3），代谢和甲基化年龄（与项目4）。 （2）表现高 透明质酸酶抑制剂的吞吐量筛选，并测试这些化合物对健康，健身和年龄的影响 小鼠相关的病理。 （3）确定负责NMR表观基因组稳定性的分子机制。我们 将识别特定的组蛋白修饰NMR中差异调节的酶，并操纵它们 稳定小鼠表观基因组。我们将与项目1合作确定SIRT6在NMR中的作用 表观基因组的稳定性，并使用项目3研究NMR和小鼠的基因组和甲基稳定性 表观遗传干预后的细胞。拟议的研究将确定出口寿命的策略 在裸痣大鼠到其他物种的机制。