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: 10399522
• 负责人: Andrei Seluanov
• 金额: $ 31.49万
• 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/10399522
• 关键词: Acids; Address; Age; Animals; Biological Assay; 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; metabolome; metabolomics; methylome; novel; rat genome; small molecule; small molecule inhibitor; transcriptome; transcriptomics; translational potential; 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.

项目2的长期目标是了解长寿的分子机制 以及长寿哺乳动物物种的癌症抵抗力，然后将这些策略应用于人类。的 裸鼹鼠（NMR）是最长寿的啮齿动物，最长寿命为32年。此外，NMR 对癌症和其他与年龄有关的疾病具有高度抵抗力。由于核磁共振与寿命短的实验室有关， 啮齿类动物，它们是研究长寿的理想模型。我们发现了一种新的癌症机制- NMR中的抗性，其由裸细胞中丰富的高分子量透明质酸（HMW-HA）介导。 鼹鼠组织HA是一种聚合物糖胺聚糖，是由细胞外基质产生的一种成分， 透明质酸合成酶2基因（HAS 2）。从NMR细胞中消耗HMW-HA使它们易于形成肿瘤。在 在当前的资助周期中，我们产生了表达裸鼹鼠HAS 2的转基因小鼠（nmrHAS 2小鼠）。我们 初步结果表明，nmrHAS 2小鼠具有更长的寿命和改善的适应性。这些小鼠 抗骨关节炎，并改善造血干细胞的维持。重要的是，我们发现， 由于非常高的透明质酸酶（HA降解），nmrHAS 2小鼠中的HMW-HA水平仅适度升高 与裸鼹鼠相比，小鼠组织中的活性。人体组织有类似的高透明质酸酶 活动因此，我们建议使用小分子下调透明质酸酶是一种有前途的策略 增加内源性HMW-HA水平，缓解年龄相关疾病，具有转化潜力。 我们设计了一种高通量筛选透明质酸酶抑制剂的策略， 这些化合物上调HMW-HA水平。为了寻找促进核磁共振健康的其他机制， 长寿，我们发现NMR具有更稳定的表观基因组，其特征在于对iPSC的抗性 重编程和组蛋白修饰的特定差异。根据这些发现，我们未来的目标 集中在我们在NMR中确定的两个长寿机制，即HMW-HA和稳定的表观基因组。 我们的目标是：（1）完成生命周期研究，表征癌症易感性、组织病理学、基因组 nmrHAS 2小鼠的稳定性（项目3）、代谢和甲基化年龄（项目4）。(2)执行高 通过筛选透明质酸酶抑制剂，并测试这些化合物对健康，健身和年龄的影响， 小鼠的相关病理学。(3)确定负责NMR表观基因组稳定性的分子机制。我们 将确定特定的组蛋白修饰酶，这些酶在NMR中受到不同的调节，并操纵它们。 来稳定小鼠的表观基因组我们将与项目1合作，以确定SIRT 6在NMR中的作用 表观基因组稳定性，并与项目3研究NMR和小鼠中的基因组和甲基化组稳定性 表观遗传干预后的细胞。拟议的研究将确定出口长寿的战略， 裸鼹鼠身上发现的机制转移到其他物种。