Program in mammalian telomere biology

哺乳动物端粒生物学项目

• 批准号: RGPIN-2017-04871
• 负责人: Riabowol, Karl
• 金额: $ 3.5万
• 依托单位: University of Calgary
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=710783
• 关键词: Program; mammalian; telomere; biology

The ends of mammalian chromosomes contain variable numbers of TTAGGG repeats. In many species this telomeric DNA is lost due to the end replication problem, as normal somatic cells replicate. When cells lose sufficient telomeric DNA, a DNA damage signal is generated, activating the ATM kinase and p53 transcription factor to block the cell cycle and induce cell replicative senescence. Senescence is thought to serve as a barrier to cell immortality and abnormal cell growth since it limits cell replicative capacity. However, short telomeres also result in genetic instability leading to a variety of diseases and large correlational studies have linked short telomeres to high rates of cell transformation. Short telomeres are also associated with early mortality, suggesting that telomere length might contribute to determining lifespan. Studies of monozygotic and dizygotic twins and elderly populations have yielded conflicting results, leaving the question of whether telomere length per se affects life span, controversial. Use of the best mammalian genetic model, mice, cannot address this issue because the dynamics of rodent telomeres differ significantly from those of most mammals including humans. We previously found that males lose telomere sequence faster than females and that telomere length in children correlates to the age of fathers at conception, providing some clues about how telomere length is set in the human population and why telomere length varies so widely in humans. However, study of human samples has limitations based on genetic and ethical considerations. We observed a strong correlation between telomere length and lifespan in a subset of the ~200 inbred dog breeds with average lifespans ranging from 5-14 years (Fick et al, Cell Reports, 2012). Our observations were possible due to the high linkage disequilibrium in dog breeds, and have provided what may be the strongest evidence to date that telomere length contributes to determining lifespan in species where telomere attrition causes cell senescence. This proof-of-principle study in canines has laid the foundation for using primary canine cell strains to test the hypothesis that cells from different breeds will divide a number of times that is proportional to the average breed lifespan, and that factors can be identified that regulate telomere dynamics in normal diploid cells. Our long-term goals are to use a subset of dog breeds to: -establish and characterize a set of primary canine cell strains. -use them to ask if telomere length and replicative lifespan affects organismal lifespan -identify candidate endogenous factors that regulate telomere length, and -target these factors to see if they selectively increase or decrease cell replicative lifespan or organismal lifespan. Once the canine model is established we will make it freely available to others working in the area of cellular aging to accelerate understanding of this area.

哺乳动物染色体的末端含有可变数目的TTAGGG重复序列。在许多物种中，端粒DNA由于末端复制问题而丢失，因为正常的体细胞复制。当细胞失去足够的端粒DNA时，产生DNA损伤信号，激活ATM激酶和p53转录因子以阻断细胞周期并诱导细胞复制性衰老。衰老被认为是细胞永生和异常细胞生长的障碍，因为它限制了细胞的复制能力。然而，短端粒也会导致遗传不稳定性，导致各种疾病，大型相关研究将短端粒与高细胞转化率联系起来。短端粒也与早期死亡有关，这表明端粒长度可能有助于决定寿命。对同卵双胞胎和异卵双胞胎以及老年人群的研究得出了相互矛盾的结果，使得端粒长度本身是否影响寿命的问题存在争议。 使用最好的哺乳动物遗传模型，小鼠，不能解决这个问题，因为啮齿动物端粒的动力学与包括人类在内的大多数哺乳动物的端粒动力学显著不同。我们以前发现男性比女性更快地失去端粒序列，并且儿童的端粒长度与父亲受孕时的年龄相关，这为端粒长度如何在人群中设置以及为什么端粒长度在人类中变化如此广泛提供了一些线索。然而，基于遗传和伦理考虑，对人类样本的研究存在局限性。 我们在约200个近交犬品种的一个子集中观察到端粒长度与寿命之间的强相关性，平均寿命范围为5-14年（Fick et al，Cell Reports，2012）。我们的观察是可能的，由于高连锁不平衡的狗品种，并提供了什么可能是最有力的证据，到目前为止，端粒长度有助于确定寿命的物种端粒磨损导致细胞衰老。这项在犬中进行的原理验证研究为使用原代犬细胞株来测试以下假设奠定了基础：来自不同品种的细胞将分裂多次，与平均品种寿命成比例，并且可以确定调节正常二倍体细胞中端粒动力学的因素。 我们的长期目标是使用一部分犬种： - 建立并表征一组原代犬细胞株。 - 使用它们来询问端粒长度和复制寿命是否影响生物体寿命 - 鉴定调节端粒长度的候选内源性因子，和 - 针对这些因素，看看它们是否选择性地增加或减少细胞复制寿命或生物体寿命。 一旦犬模型建立，我们将免费提供给其他在细胞衰老领域工作的人，以加速对这一领域的理解。