A mouse model with humanized telomere homeostasis

摘要 该项目的目标是开发一种获得与人类相似的端粒的小鼠模型 动态平衡用于研究人类衰老、癌症和其他与年龄有关的疾病。在人类身上， 大多数体细胞缺乏端粒酶的表达，不能补充端粒。端粒 在连续的细胞分裂时逐渐缩短，起到老化时钟的作用。 因此，端粒磨损是人类衰老和端粒稳定的关键因素， 主要通过端粒酶的激活，是多发性硬化症发生发展过程中的重要事件。 人类癌症。另一方面，许多其他的生物，包括实验室的老鼠，并不是这样。 表现出端粒介导的复制衰老。小鼠有很长的端粒和无处不在的 成人组织中的端粒酶活性。这种物种间的差异已经成为 利用小鼠解决人类衰老和癌症生物学中的许多基本问题 模特们。为了应对这一挑战，我们已经开始创造一种人性化的老鼠品系 端粒动态平衡。我们已经设计了一个人源化的小鼠TERT等位基因(HmTert)，通过使用 来自人类TERT基因(HTERT)的调控序列来取代他们的小鼠 对口单位。我们发现hmTert基因的调控与hTERT基因的调控类似。 在小鼠发育过程中和在小鼠成年组织中。值得注意的是，hmTert等位基因施加了 小鼠的端粒长度设定点比野生型mTert基因短得多。在此应用程序中， 我们提出了三个具体的目标：1)创造一个具有hmTert等位基因和类人的小鼠品系 2)利用人源化端粒稳态研究小鼠的复制衰老；以及3) 用人源化端粒测定小鼠的寿命和健康寿命。

Abstract The goal of this project is to develop a mouse model that acquires human-like telomere homeostasis for the study of human aging, cancer, and other age-related diseases. In humans, most somatic cells lack telomerase expression and cannot replenish their telomeres. Telomeres progressively shorten upon successive cell divisions, functioning as an aging clock. Consequently, telomere attrition is a critical factor of human aging and telomere stabilization, predominantly via telomerase activation, is an essential event in the development of most human cancers. On the other hand, many other organisms, including laboratory mice, do not exhibit telomere-mediated replicative aging. Mice possess long telomeres and ubiquitous telomerase activity in adult tissues. This interspecies difference has become a bottleneck for addressing many fundamental questions in human aging and cancer biology using mouse models. To tackle this challenge, we have started to create a mouse strain with humanized telomere homeostasis. We have engineered a humanized mouse Tert allele (hmTert) by using regulatory sequences from the human TERT gene (hTERT) to replace their mouse counterparts. We found that the hmTert gene regulation recapitulated that of the hTERT gene during mouse development and in mouse adult tissues. Remarkably, the hmTert allele imposed a much shorter telomere length setpoint than the wildtype mTert gene in mice. In this application, we propose three specific aims: 1) Create a mouse strain with hmTert alleles and human-like short telomeres; 2) Study replicative aging in mice with humanized telomere homeostasis; and 3) Determine lifespan and health-span of mice with humanized telomeres.