Telomeres function as an aging clock because most human somatic cells lack telomerase expression and their telomeres progressively shorten upon successive cell divisions. Accordingly, telomere shortening is a critical factor of human aging and telomerase activation is essential for the development of many human cancers. On the other hand, cells from some other organisms, including mice, do not exhibit telomere-mediated replicative aging. Mice possess long heterogeneous telomeres and ubiquitous telomerase activities in somatic tissues. This inter-species difference has become a bottleneck for addressing many fundamental questions in human aging and cancer biology using mouse models. Thus, the long-term goal of this project is to genetically engineer mouse strains with human-like telomere homeostasis and to test the hypothesis that short telomeres and repressed telomerase confer replicative aging in mice. Our recent studies have identified several distal regulatory elements critical for the repression of hTERT gene. In this proposal, we will test the hypothesis that incorporation of these elements into their corresponding mouse genomic sites leads to human-like TERT gene regulation in mice. We will first engineer mouse embryonic stem cells (ESCs) with a humanized mTERT locus (hmTERT) and then use these ESCs to generate mouse strains with human-like telomerase regulation. The regulation of hmTERT locus will be determined both during in vitro ESC differentiation and during mouse development. We anticipate that these mice will serve as an improved model for studying human aging and cancer.

Public Health Relevance

Mice have much longer telomeres than humans. While telomere shortening is a key mechanism of human aging, cells from some other organisms, including laboratory mice, do not exhibit telomere-mediated aging. In this application, we plan to genetically engineer mouse strains with human-like telomerase regulation. Such mice should become an improved model for studying human aging and cancer.

Agency
National Institute of Health (NIH)
Institute
Office of The Director, National Institutes of Health (OD)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21OD021432-02
Application #
9146425
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Moro, Manuel H
Project Start
2015-09-18
Project End
2017-07-31
Budget Start
2016-08-01
Budget End
2017-07-31
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Washington State University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
041485301
City
Pullman
State
WA
Country
United States
Zip Code
99164