The termini of most eukaryotic chromosomes are composed of terminal repeats called telomeres. These repeats serve to protect chromosome integrity and ensure complete replication of essential genes. Although the molecular basis of aging or replicative senescence is not fully understood, reductions in telomere length are thought to play an important role. For example, telomeres are shorter in somatic tissues from older than from younger individuals. Children born with Hutchinson-Gilford progeria, an early-aging syndrome, have shorter telomeres than do age-matched controls. In other aging-genetics disorders, such as Werner's syndrome and Down's syndrome, cells lose telomeres at two to three times the rate in age-matched controls. Telomeric repeats are produced de novo by the ribonucleoprotein enzyme telomerase. The ectopic expression of telomerase in normal human somatic cells results in an extended lifespan and inhibition of replicative senescence. Telomeres also shorten in hematopoietic stem cells during normal aging and in the hematopoietic cells of young patients who have received allogenic bone marrow transplant. We postulate that if we can experimentally elongate the telomere ex vivo in normal human hematopoietic cells, replicative capacity and self-renewal potential may increase and thus alter the incidence and/or time of onset of age related hematopoietic disorders and immunosenescence. We propose to develop a mouse model system that permits the study of telomerase function in human hematopoietic cells. To this end, we will make use of the NOD/SCID mouse model in which the hematopoietic compartment can be reconstituted with human hematopoietic stem cells. Retroviral methods will be used to direct altered telomerase activity in these transplanted hematopoietic stem cells and their mature derivatives. The applicant is an M.D. who will have completed a residency in anatomic pathology with subspecialty training in hematopathology prior to the proposed start date. He also holds a Ph.D. in Biochemistry. The research will be carried out in a cancer/aging biology laboratory within the Dana-Farber Cancer Institute, an affiliate of the Harvard Medical School, under the mentorship of Dr. Ron DePinho.
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