A mouse model with humanized telomere homeostasis

摘要 这个项目的目标是开发一个小鼠模型，获得类似人类的端粒 人体老化、癌症和其他与年龄有关的疾病的研究。在人类中， 大多数体细胞缺乏端粒酶表达并且不能补充它们的端粒。端粒 在连续的细胞分裂中逐渐缩短，起到衰老时钟的作用。 因此，端粒磨损是人类衰老和端粒稳定的关键因素， 主要通过端粒酶激活，是大多数肿瘤发生发展中的重要事件。 人类癌症另一方面，许多其他生物，包括实验室小鼠， 表现出端粒介导的复制性衰老。老鼠拥有很长的端粒， 成人组织中端粒酶活性。这种物种间的差异已经成为 使用小鼠来解决人类衰老和癌症生物学中的许多基本问题 模型为了应对这一挑战，我们已经开始创造一种小鼠品系， 端粒内稳态我们已经通过使用人源化的小鼠Tert等位基因（hmTert）， 人端粒酶逆转录酶基因（hTERT）的调控序列，以取代他们的小鼠 同行我们发现hmTert基因的调控与hTERT基因的调控相似， 在小鼠发育期间和小鼠成年组织中。值得注意的是，hmTert等位基因 在小鼠中，端粒长度设定值比野生型mTert基因短得多。在本申请中， 我们提出了三个具体的目标：1）创建一个具有hmTert等位基因和人类样基因的小鼠品系。 短端粒; 2）在具有人源化端粒稳态的小鼠中研究复制性衰老;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.