The role of hyaluronan in longevity and cancer resistance of longest-lived rodent

项目2的目标是了解长寿和癌症的分子机制 长寿啮齿动物的抵抗力。裸鼹鼠是寿命最长的啮齿类动物， 寿命32年。此外，裸鼹鼠对癌症有很强的抵抗力。因为裸鼹鼠 它们与寿命短、易患癌症的实验室啮齿动物有关，是研究的理想模型。 长寿和癌症抵抗力。我们在裸鼹鼠身上发现了一种新的抗癌机制 大鼠称为早期接触抑制（EC 1）。裸鼹鼠细胞对接触抑制非常敏感， 在低细胞密度下抑制增殖。EC 1与pi 6“（pl 6）的诱导相关。我们发现细胞 和另一种长寿的啮齿动物盲鼹鼠一样， 极高分子量透明质酸（HMW-HA），其是ECl所需的。HA的特性 取决于聚合物长度，较长的聚合物更有利。值得注意的是，裸鼹鼠 是小鼠或人类HA的六倍多。我们发现HMW-HA可以保护细胞免受氧化损伤， HA的应激和释放导致裸鼹鼠细胞形成肿瘤。基于这些发现，我们 推测HMW-HA在裸鼹鼠寿命和癌症抗性中起关键作用。我们 目的：（1）确定HA导致细胞周期阻滞和ECl的信号通路。我们将测试 假设HMW-HA信号通过CD 44受体激活pi 6表达，并鉴定中间体 信号事件。在与项目4的合作中，我们将从HA和pi 6信号通路中识别基因。 其被HMW-HA激活并检查其对体内细胞周期停滞的作用。(2)确定机制 负责HMW-HA的细胞保护特性。我们假设除了是一个 ROS的细胞外清除剂，HMW-HA触发信号传导事件，其抑制细胞凋亡或 激活细胞内的抗氧化机制。我们将确定HA信号传导的目标，并测试是否 裸鼹鼠HAS 2的表达改善小鼠的氧化应激抗性。协同 项目四我们将分析裸鼹鼠中差异表达的应激信号基因。在 与项目3合作，我们将确定HA是否具有抗突变作用。(3)测试是否 来自裸鼹鼠的HMW-HA的有益效果可以转移到其它哺乳动物。我们将使用两个 方法：产生表达裸鼹鼠HAS 2的转基因小鼠或用透明质酸酶处理小鼠 抑制剂的我们将测试这些治疗是否改善小鼠癌症和/或应激抵抗力。 相关性（参见说明）： 裸鼹鼠是最长寿的啮齿动物，最长寿命为32岁。除了其 裸鼹鼠的寿命长，对癌症有着非凡的抵抗力，因为肿瘤从来没有 在这些啮齿动物身上观察到的。项目2的目标是了解非凡的背后的机制， 裸鼹鼠对癌症的抵抗力我们希望对长寿哺乳动物物种的研究 解开癌症抵抗和长寿的机制，将用于延长人类寿命。

The goal of Project 2 is to understand the molecular mechanisms responsible for longevity and cancer resistance of long-lived rodents. Naked mole rat is the longest-lived rodent species with the maximum lifespan of 32 years. Furthermore, naked mole rats are highly resistant to cancer. Since naked mole rats are related to the short-lived and cancer-prone laboratory rodents, they represent an ideal model for the studies of longevity and cancer resistance. We identified a novel mechanism of cancer-resistance in the naked mole rat termed early contact inhibition (ECl). Naked mole rat cells are hypersensitive to contact inhibition and arrest proliferation at low cell density. ECl is associated with induction of pi6'^'^"^ (p16). We found that cells of the naked mole rat, as well as another long-lived rodent the blind mole rat, secrete large amounts of extremely high molecular weight hyaluronan (HMW-HA), which is required for ECl. The properties of HA depend on the polymer length, with longer polymers being more beneflcial. Remarkably, naked mole rat HA is over six times longer than mouse or human HA. We show that HMW-HA protects cells from oxidative stress and rehioval of HA causes naked mole rat cells to form tumors. Based on these findings, we hypothesize that that HMW-HA plays a key role in the naked mole rat longevity and cancer resistance. Our aims are: (1) Determine signaling pathways leading from HA to cell cycle arrest and ECl. We will test the hypothesis that HMW-HA signaling via CD44 receptor activates expression of pi6, and identify intermediate signaling events. In collaboration with Project 4 we will identify genes from HA and pi6 signaling pathways that are activated by HMW-HA and examine their effect on cell cycle arrest in vivo. (2) Identify mechanisms responsible for cytoprotective properties of HMW-HA. We hypothesize that in addition to being an extracellular scavenger of ROS, HMW-HA triggers signaling events that either suppress apoptosis or activate intacellular antioxidant machinery. We will identify the targets of HA signaling, and test whether expression of naked mole rat HAS2 improves oxidative stress resistance in mice. In collaboration with Project 4 we will analyze the stress-signaling genes showing differential expression in the naked mole rat. In collaboration with Project 3 we will determine whether HA has anti-mutagenic effect. (3) Test whether beneficial effects of HMW-HA from the naked mole rat can be transferred to other mammals. We will use two approaches: generate transgenic mice expressing naked mole rat HAS2 or treat mice with hyaluronidase inhibitors. We will test whether these treatments improve mouse cancer and/or stress resistance. RELEVANCE (See instructions): The naked mole rat is the longest living rodent with the maximum lifespan of 32 years. In addition to its longevity, the naked mole rat has an extraordinary resistance to cancer as tumors have never been observed in these rodents. The goal of Project 2 is to understand the mechanisms behind the extraordinary resistance to cancer in the naked mole rat. We expect that investigation of long-lived mammalian species will unravel mechanisms of cancer resistance and longevity that will be applied to extend human lifespan.