Program in mammalian telomere biology

哺乳动物染色体末端含有数量可变的TTAGGG重复序列。在许多物种中，这种端粒DNA由于末端复制问题而丢失，因为正常的体细胞进行复制。当细胞失去足够的端粒DNA时，就会产生DNA损伤信号，激活ATM激酶和P53转录因子，阻止细胞周期，诱导细胞复制衰老。衰老被认为是阻止细胞永生和细胞异常生长的屏障，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，导致多种疾病，大量相关研究表明，短端粒与高细胞转化率有关。端粒较短也与早期死亡有关，这表明端粒长度可能有助于决定寿命。对同卵和异卵双胞胎和老年人群的研究产生了相互矛盾的结果，留下了端粒长度本身是否会影响寿命的争议。 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态与包括人类在内的大多数哺乳动物的端粒动态显著不同。我们之前发现，男性比女性更快地丢失端粒序列，儿童的端粒长度与受孕时父亲的年龄有关，这为人类群体中端粒长度的设定以及为什么端粒长度在人类中变化如此之大提供了一些线索。然而，基于遗传和伦理方面的考虑，对人体样本的研究存在局限性。 我们在大约200个近交系犬种中观察到端粒长度和寿命之间的强烈相关性，这些近交系犬种的平均寿命从5-14年不等(Fick等人，Cell报告，2012年)。我们的观察是可能的，因为在狗品种中存在高度连锁不平衡，并提供了可能是迄今为止最有力的证据，证明端粒长度有助于决定端粒磨损导致细胞衰老的物种的寿命。这项在犬身上进行的原则验证性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，与平均繁殖寿命成正比，并且可以确定调节正常二倍体细胞端粒动态的因素。 我们的长期目标是利用狗品种的子集来： -建立并鉴定一组原代犬细胞株。 -使用它们来询问端粒长度和复制寿命是否影响生物寿命 -确定调节端粒长度的候选内源性因素，以及 -以这些因素为目标，看看它们是有选择地增加或减少细胞复制寿命或生物寿命。 一旦犬类模型建立，我们将把它免费提供给其他在细胞衰老领域工作的人，以促进对这一领域的理解。

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.