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

项目2的目标是了解导致长寿和癌症的分子机制 长寿啮齿动物的抵抗力。裸鼠是最长寿的啮齿动物物种， 寿命为32年。此外，裸鼠对癌症具有很强的抵抗力。因为裸鼠是 与寿命短且易患癌症的实验室啮齿动物有关，它们代表了研究的理想模型 长寿和抗癌的能力。我们在裸鼠体内发现了一种新的抗癌机制 大鼠称为早期接触抑制(ECL)。裸鼠细胞对接触抑制和 在低细胞密度下抑制增殖。ECL与pi6‘^’^“^(P16)的诱导有关。 裸鼠，以及另一种长寿啮齿动物盲鼠，分泌大量的 ECL所需的超高相对分子质量透明质酸(HMW-HA)。腐植酸的性质 取决于聚合物的长度，聚合物越长越有利。值得注意的是，裸鼠HA 比老鼠或人的HA长六倍以上。我们发现HMW-HA可保护细胞免受氧化 HA的应激和修复可导致裸鼠葡萄胎细胞形成肿瘤。基于这些发现，我们 假设HMW-HA在裸鼠寿命和抗癌能力中起关键作用。我们的 目的是：(1)确定从HA到细胞周期停滞和ECL的信号通路。我们将测试 假设HMW-HA信号通过CD44受体激活PI6的表达，并识别中间产物 信号事件。在与项目4的合作中，我们将确定HA和PI6信号通路的基因 并检测它们在体内对细胞周期停滞的影响。(二)找准机制 负责HMW-HA的细胞保护性能。我们假设除了成为一名 细胞外ROS清除剂，HMW-HA触发信号事件，抑制细胞凋亡或 激活细胞内的抗氧化机制。我们将确定HA信令的目标，并测试 裸鼠HAS2的表达提高了小鼠的氧化应激抵抗能力。与 项目4，我们将分析在裸鼠体内显示差异表达的应激信号基因。在……里面 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 裸鼠体内的HMW-HA的有益作用可以转移到其他哺乳动物身上。我们将使用两个 方法：建立表达裸鼠HAS2的转基因小鼠或用透明质酸酶治疗小鼠 抑制剂。我们将测试这些治疗方法是否可以改善小鼠癌症和/或抗应激能力。 相关性(请参阅说明)： 裸鼠是最长寿的啮齿动物，最长寿命为32岁。除了它的 长寿，裸鼠对癌症具有非凡的抵抗力，是肿瘤从未有过的 在这些啮齿动物身上观察到的。项目2的目标是了解非同寻常的 裸鼠对癌症的抵抗力。我们预计，对长寿哺乳动物物种的调查将 解开抗癌和长寿的机制，这将被应用于延长人类寿命。

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.