The goal of these studies is to test the telomere hypothesis: Cellular senescence is triggered by the shortening of telomere repeats to a critical length due to loss of telomerase function while cellular immortalization involves telomerase reactivation. The objectives of this proposal are : i) to assess the role of telomerase in the growth and development of normal cells during embryogenesis, ii) in the homeostasis of established organ systems of the adult and iii) to determine the requirement for telomerase activity in neoplasia. To achieve these objectives, Dr. De Pinho will make use of a knockout mouse model which is homozygous null for the gene encoding the essential RNA primer component of telomerase. The developmental and physiological consequences of telomerase deficiency will be monitored in organ systems that posses significant regenerative capacity. The cancer aspect of telomerase deficiency will be determined by breeding these mice with several well-established cancer-prone models.
