A mouse model with humanized telomere homeostasis

具有人源化端粒稳态的小鼠模型

• 批准号: 10701695
• 负责人: JIYUE ZHU
• 金额: $ 45.12万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10701695
• 关键词: Address; Adult; Affect; Aging; Alleles; Cancer Biology; Catalytic Domain; Cell Aging; Cell Differentiation process; Cell Survival; Cell division; Cells; Chromosomal Stability; Complex; Cross-Sectional Studies; DNA; Data; Defect; Development; Disease; Distal; Elements; Engineering; Epigenetic Process; Equilibrium; Event; Fibroblasts; Gene Expression Regulation; Generations; Genes; Genetic; Genetic Transcription; Genetic study; Genetically Engineered Mouse; Goals; Homeostasis; Human; Knockout Mice; Laboratory Study; Laboratory mice; Length; Link; Longevity; Longitudinal Studies; Malignant Neoplasms; Mediating; Modeling; Mouse Strains; Mus; Organism; Pathogenesis; Process; Proteins; RNA; Regulation; Regulatory Element; Reporter Genes; Repression; Research; Somatic Cell; Study models; TERT gene; Telomerase; Telomere Shortening; Testing; Tissues; Trans-Activators; Transgenic Organisms; Tumor Suppression; age related; embryonic stem cell; healthspan; human disease; human tissue; humanized mouse; hybrid gene; improved; in vivo; mouse development; mouse model; telomere; transmission process; tumorigenic

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.

抽象的 该项目的目标是开发一种获得类人端粒的小鼠模型 用于研究人类衰老、癌症和其他与年龄相关的疾病的稳态。在人类中， 大多数体细胞缺乏端粒酶表达，无法补充端粒。端粒 随着连续的细胞分裂而逐渐缩短，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，是大多数发育过程中的一个重要事件 人类癌症。另一方面，许多其他生物体，包括实验室小鼠，并不 表现出端粒介导的复制衰老。小鼠拥有长端粒并且无处不在 成人组织中的端粒酶活性。这种种间差异已成为瓶颈 使用小鼠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，我们已经开始创建具有人源化的小鼠品系 端粒稳态。我们通过使用设计了人源化小鼠 Tert 等位基因 (hmTert) 人类 TERT 基因 (hTERT) 的调控序列取代了小鼠 同行。我们发现 hmTert 基因的调控再现了 hTERT 基因的调控 在小鼠发育期间和小鼠成年组织中。值得注意的是，hmTert 等位基因强加 与小鼠中的野生型 mTert 基因相比，端粒长度设定点要短得多。在这个应用程序中， 我们提出了三个具体目标：1）创建具有 hmTert 等位基因和类人小鼠品系 端粒短； 2）研究具有人源化端粒稳态的小鼠的复制衰老；和 3) 确定具有人源化端粒的小鼠的寿命和健康寿命。