Body size, longevity, and cancer resistance in animals

动物的体型、寿命和抗癌能力

• 批准号: RGPIN-2020-06472
• 负责人: Wood, Geoffrey
• 金额: $ 2.33万
• 依托单位: University of Guelph
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=761932
• 关键词: Body; size; longevity; cancer; resistance

Every time a cell divides there is the risk that, either through chance or chemical damage to DNA, the cell will sustain a mutation. When enough specific mutations occur in a cell's DNA, cancer develops. Based on this, one would expect that large sized animals and/or animals with a long lifespan would be at high risk of developing cancer, since they have more cells dividing and more cell divisions over their lifetime - however, this is not always the case. The largest animals that have ever lived, the bowhead, blue and other whales, have lifespans that exceed 100 years, yet have 1000-fold more cells than a human and only rarely develop cancer. Likewise, African elephants, which are 100 times heavier than humans, have less than half the incidence of cancer. This lack of association between body size, longevity, and cancer incidence is often referred to as Peto's paradox. Elephants and some whales have multiple functional copies of tumour suppressor genes, as do some long-lived bats. The proteins produced by these genes counteract the factors that promote cancer development. The goal of my research program is to explore the mechanisms underlying the lower than expected cancer incidence in large and/or long-lived animals. We have assembled a unique and diverse collection of tumours that arose in large and/or long-lived animals ranging from whales to parrots to bats, and in this research program we will compare tumour suppressor gene copy numbers in these animals to those that do not have a long lifespan for their size, such as dogs and mice. We will measure expression of the genes, assess their function in cell culture by removing specific genes, test each species' cells response to DNA damaging agents, and measure how readily the cells are transformed. The research laid out in this program is designed to yield fundamental new knowledge of how organisms with large body size and/or long lifespan resist development of cancer. My long-term goals are to apply evolutionary comparative methods to test potential relationships between longevity and tumour suppressor gene copy number and expression. This will help us to understand the importance of patterns in gene copies that repeat during evolutionary history.

每当细胞分裂时，都存在这样的风险，即由于偶然或化学物质对DNA的破坏，该细胞将保持突变。当一个细胞的DNA发生足够多的特定突变时，癌症就会发生。基于这一点，人们会认为大型动物和/或寿命长的动物将面临患癌症的高风险，因为它们在一生中有更多的细胞分裂和更多的细胞分裂-然而，情况并不总是如此。有史以来最大的动物，弓头鲸、蓝鲸和其他鲸鱼，寿命超过100年，但拥有的细胞是人类的1000倍，而且很少会患癌症。同样，非洲象的体重是人类的100倍，其癌症发病率不到人类的一半。这种体型、寿命和癌症发病率之间缺乏联系的现象通常被称为皮托悖论。大象和一些鲸鱼和一些长寿蝙蝠一样，具有多种肿瘤抑制基因的功能副本。这些基因产生的蛋白质抵消了促进癌症发展的因素。我的研究计划的目标是探索大型和/或长寿动物癌症发病率低于预期的机制。我们汇集了从鲸鱼到鹦鹉再到蝙蝠等大型和/或长寿动物身上出现的独特和多样化的肿瘤，在这个研究项目中，我们将比较这些动物和那些与它们的大小相比寿命不长的动物的肿瘤抑制基因拷贝数。我们将测量这些基因的表达，通过移除特定基因来评估它们在细胞培养中的功能，测试每个物种的细胞对DNA损伤剂的反应，并测量细胞转化的难易程度。这项计划中的研究旨在产生关于体型较大和/或寿命较长的生物体如何抵抗癌症发展的基本新知识。我的长期目标是应用进化比较方法来测试长寿和肿瘤抑制基因拷贝数和表达之间的潜在关系。这将帮助我们理解在进化史上重复的基因复制模式的重要性。