Collaborative Research: Determining the role of ER stress in the evolution of large bodies and long lifespans

合作研究：确定内质网应激在大型身体和长寿命进化中的作用

• 批准号: 2028459
• 负责人: Scott Glaberman
• 金额: $ 36.64万
• 依托单位: George Mason University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2028459&HistoricalAwards=false
• 关键词: Collaborative; Research; Determining; role; ER

A major goal of biology is to understand the diversity of life on earth. Body size and longevity are two traits that vary tremendously across animals. Some species weigh less than a gram or live only several weeks, while others weigh thousands of kilograms or live for several hundred years. What could cause such remarkable variation in body size and lifespan? Turtles are a promising group to study this question because some species are extremely small, while others, like Galapagos tortoises, are gigantic and long-lived. Previous research suggests that Galapagos tortoises, along with some other large, long-lived animals like elephants, are particularly good at removing old or damaged cells from their bodies before they harm the individual – a process called “apoptosis”. In this project, the genomes of many turtle species will be compared to identify genes that may be responsible for the unique behavior of Galapagos tortoise cells. The effects of these genes will then be disrupted in Galapagos tortoise cells to see if it makes them behave more like other turtle cells. The goal is to characterize genes that can help explain the extraordinary diversity in body size and lifespan among animals. The results can also have important biomedical implications, since the same genes related to longevity may also be involved in aging related diseases and cancer. The project has a large outreach component including bioinformatics boot camps for high school students, freely available classroom case studies about the biology of longevity, and educational panels at zoos.Body size and longevity vary tremendously across animals, but the mechanisms underlying this variation are not well understood. At one extreme, certain species such as Galapagos and Aldabra giant tortoises have evolved remarkably large body sizes and long lifespans, despite the increased genotoxic and cytotoxic stress that comes with living longer and having more cells. Giant tortoises live approximately 3-5 times longer and weigh 50-100 times more than their closest relatives. Recent evidence suggests that Galapagos tortoises respond differently to endoplasmic reticulum (ER) stress, a set of events leading to the deregulation of protein homeostasis and one of the hallmarks of aging and reduced lifespan. Galapagos tortoises rapidly induce apoptosis in response to ER stress compared to cells from smaller, shorter-lived turtle species. In this project, comparative genomics will be used to identify ER stress-related genes that have been positively selected or duplicated/lost in large, long-lived tortoises versus their smaller, shorter-lived relatives. Genome editing will be used to knock down and characterize the cellular functions of ER stress candidate genes in turtle cell lines. The immediate aim is to identify the processes through which large, long-lived turtles have dealt with physiological constraints on body size and lifespan. The overarching goal is to discover the mechanisms underlying the extraordinary diversity in animal body size and longevity observed in nature.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

生物学的一个主要目标是了解地球上生命的多样性。体型和寿命是两个在动物中差异很大的特征。有些物种的体重不到一克，或者只能活几个星期，而另一些则重达数千公斤，或者可以活几百年。是什么导致了如此显著的体型和寿命差异呢？海龟是研究这个问题的一个很有希望的群体，因为有些物种非常小，而其他物种，如加拉帕戈斯龟，是巨大的和长寿的。先前的研究表明，加拉帕戈斯陆龟，沿着的还有其他一些大型长寿动物，如大象，特别擅长在它们伤害个体之前从它们的身体中去除旧的或受损的细胞--这一过程被称为“凋亡”。在这个项目中，许多海龟物种的基因组将被比较，以确定可能负责加拉帕戈斯海龟细胞独特行为的基因。这些基因的作用将在加拉帕戈斯龟细胞中被破坏，看看它是否使它们的行为更像其他龟细胞。其目标是描述基因的特征，这些基因可以帮助解释动物在体型和寿命方面的非凡多样性。这些结果也可能具有重要的生物医学意义，因为与长寿相关的相同基因也可能与衰老相关的疾病和癌症有关。该项目有一个很大的外展部分，包括高中生的生物信息学靴子营地，免费提供的课堂案例研究长寿的生物学，和教育小组在动物园。身体大小和寿命在动物之间有很大的差异，但这种差异背后的机制还没有很好的理解。在一个极端，某些物种，如加拉帕戈斯和阿尔达伯拉巨龟已经进化出非常大的体型和长寿命，尽管随着寿命的延长和细胞数量的增加，遗传毒性和细胞毒性压力也在增加。巨龟的寿命大约是其近亲的3-5倍，体重是其近亲的50-100倍。最近的证据表明，加拉帕戈斯龟对内质网（ER）应激的反应不同，内质网应激是一系列导致蛋白质稳态失调的事件，也是衰老和寿命缩短的标志之一。加拉帕戈斯龟快速诱导细胞凋亡响应ER压力相比，细胞较小，寿命较短的海龟物种。在这个项目中，比较基因组学将用于识别ER应激相关基因，这些基因在大型长寿陆龟与其较小的短命亲属中被积极选择或复制/丢失。基因组编辑将用于敲除和表征海龟细胞系中ER应激候选基因的细胞功能。目前的目标是确定大型长寿海龟处理身体大小和寿命的生理限制的过程。其首要目标是发现自然界中观察到的动物体型和寿命异常多样性的潜在机制。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。