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

透明质酸在最长寿啮齿动物的寿命和抗癌性中的作用

• 批准号: 8707607
• 负责人: Andrei Seluanov
• 金额: $ 31.08万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 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/8707607
• 关键词: Acetylglucosamine; Acids; Aging; Antioxidants; Apoptosis; Biological; CD44 gene; Cell Cycle Arrest; Cell Death; Cell Density; Cell Proliferation; Cell Surface Receptors; Cells; Collaborations; Contact Inhibition; Disaccharides; Event; Excision; Extracellular Matrix; Genes; Genome; Goals; Heart; Human; Hyaluronan; Hyaluronic Acid; Hyaluronidase; Inflammation; Instruction; Investigation; Laboratories; Length; Life; Longevity; Malignant - descriptor; Malignant Neoplasms; Mammals; Mediating; Modeling; Mole Rats; Molecular; Molecular Weight; Mus; Neoplasm Metastasis; Neoplasms; Oxidative Stress; Participant; Pathway interactions; Phenotype; Play; Polymers; Positioning Attribute; Principal Investigator; Property; Resistance; Rodent; Role; Signal Pathway; Signal Transduction; Skin; Stress; Study models; Testing; Time; Tissues; Transgenic Mice; Tumor Suppressor Proteins; anticancer research; base; biological adaptation to stress; blind; comparative; extracellular; improved; in vivo; inhibitor/antagonist; novel; oxidative damage; receptor; tumor

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.

项目2的目标是了解负责寿命和癌症的分子机制 长寿啮齿动物的抗性。裸mole大鼠是寿命最长的啮齿动物物种 32年的寿命。此外，裸痣大鼠对癌症具有高度抗性。由于裸鼠老鼠是 与短暂且容易发生癌症的实验室啮齿动物有关，它们代表了研究的理想模型 寿命和抗癌的寿命。我们确定了裸痣中抗癌的新机制 大鼠称为早期接触抑制（ECL）。裸摩尔大鼠细胞对接触抑制作用过敏和 在低细胞密度下阻止增殖。 ECL与pi6'^'^“^”^^（p16）有关。我们发现细胞 裸mole大鼠以及另一个长寿命的盲鼠大鼠，分泌大量 ECL所需的极高的分子量透明质酸（HMW-HA）。 HA的特性 取决于聚合物长度，较长的聚合物更有益。值得注意的是，裸痣老鼠ha 比老鼠或人类长六倍。我们表明，HMW-HA可保护细胞免受氧化的影响。 HA的压力和重新释放会导致裸摩尔大鼠细胞形成肿瘤。基于这些发现，我们 假设HMW-HA在赤裸的摩尔大鼠寿命和癌症耐药性中起关键作用。我们的 目的是：（1）确定从HA到细胞周期停滞和ECL导致的信号通路。我们将测试 假设HMW-HA通过CD44受体信号传导激活PI6的表达，并鉴定中间体 信号事件。与项目4合作，我们将确定HA和PI6信号通路的基因 由HMW-HA激活的，并检查其对体内细胞周期停滞的影响。 （2）确定机制 负责HMW-HA的细胞保护特性。我们假设这是一个 ROS的细胞外清除，HMW-HA触发信号事件，可抑制凋亡或 激活细胞抗氧化剂机械。我们将确定HA信号的目标，并测试是否 裸摩尔大鼠HAS2的表达改善了小鼠的氧化应激抗性。与 项目4我们将分析显示赤摩尔大鼠中差异表达的应力信号基因。在 与项目3合作，我们将确定HA是否具有抗溶血效应。 （3）测试是否 HMW-HA从裸摩尔大鼠中的有益作用可以转移到其他哺乳动物上。我们将使用两个 方法：生成表达裸鼠大鼠has2或用透明质酸酶处理小鼠的转基因小鼠 抑制剂。我们将测试这些治疗方法是否改善了小鼠癌和/或抗压力。 相关性（请参阅说明）： 裸mole大鼠是最长的活啮齿动物，其寿命为32年。除了它的 长寿，裸mole老鼠对癌症具有极大的抵抗力，因为肿瘤从未有过 在这些啮齿动物中观察到。项目2的目标是了解特殊的机制 裸鼠大鼠对癌症的抗性。我们期望对长寿哺乳动物物种进行调查 将应用于延长人类寿命的癌症耐药性和寿命的解体机制。