权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

基本信息

批准号：
2028458
负责人：
Vincent Lynch
金额：
$ 31.12万
依托单位：
SUNY at Buffalo
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=2028458&HistoricalAwards=false
关键词：
Collaborative Research Determining role ER

项目摘要

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。体型和寿命是动物之间差异巨大的两个特征。一些物种的体重不到一克，或者只活了几周，而另一些物种的体重达到数千公斤，或者活了几百年。是什么导致了体型和寿命如此显著的差异？海龟是一个很有希望研究这个问题的群体，因为一些物种非常小，而另一些物种，如加拉帕戈斯群岛的乌龟，则是巨大而长寿的。此前的研究表明，加拉帕戈斯象龟和大象等其他大型长寿动物一样，尤其擅长在伤害个体之前将老化或受损的细胞从身体中移除--这一过程被称为“细胞凋亡”。在这个项目中，将对许多海龟物种的基因组进行比较，以确定可能导致加拉帕戈斯乌龟细胞独特行为的基因。然后，这些基因的作用将在加拉帕戈斯海龟细胞中被破坏，看看它是否使它们的行为更像其他海龟细胞。其目标是确定基因的特征，以帮助解释动物之间在体型和寿命上的非凡差异。这一结果还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推广部分，包括针对高中生的生物信息学新兵训练营，关于长寿生物学的免费课堂案例研究，以及动物园的教育小组。不同动物的身体尺寸和寿命差异巨大，但这种差异背后的机制尚不清楚。在一个极端的情况下，某些物种，如加拉帕戈斯和亚达布拉巨龟，已经进化出非常巨大的身体和很长的寿命，尽管随着寿命延长和拥有更多细胞而带来的遗传毒性和细胞毒性压力增加。巨型乌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，加拉帕戈斯乌龟对内质网(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。与较小、寿命较短的乌龟物种的细胞相比，加拉帕戈斯乌龟在内质网压力下迅速诱导细胞凋亡。在这个项目中，比较基因组学将被用来识别与内质网应激相关的基因，这些基因在大型、长寿的乌龟中被积极选择或复制/丢失，而它们的亲缘关系较小、寿命较短。基因组编辑将被用来敲除和表征海龟细胞系中内质网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。总的目标是发现自然界中观察到的动物身体大小和寿命的非凡多样性背后的机制。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。