Despite an increase in the repertoire of cytotoxic and targeted therapies, the prognosis for patients with advanced malignancies remains poor. Recent work has supported a stem cell theory for cancer and suggests that an early tissue specific stem cell is the site of accumulation of the genetic alterations that lead to malignancy. The molecular determinants of stem cells in health and cancer are not known. Telomerase is a specialized DNA polymerase responsible for telomere addition by using an intrinsic RNA template. The majority of cancers express telomerase to offset telomere attrition. Aplastic anemia is the prototype stem cell failure disorder characterized by an acellular bone marrow. Recently, families with autosomal dominant dyskeratosis congenita have been found to have mutations in the telomerase RNA gene. These families display dominant inheritance of aplastic anemia, idiopathic pulmonary fibrosis as well as an increased risk of cancer. Furthermore, there is anticipation, an earlier and worse onset of symptoms with each generation, and this correlates with telomere shortening. This disease has underscored the critical role of telomeres in maintaining stem cell compartments. We recently identified a large kindred with dyskeratosis congenita that harbors a mutation in hTERT, the protein component of telomerase. This pedigree displays dominant inheritance of aplastic anemia and idiopathic pulmonary fibrosis with anticipation. The following proposal capitalizes on clinical observations made in this pedigree as well as on recent findings in a telomerase knockout mouse that models this disease. Unlike the previously engineered telomerase knockout mouse on the inbred strain, the wild-derived Castaneus mouse with telomere lengths similar to humans displays stem cell failure in the bone marrow and gastrointestinal tract. In the gastrointestinal tract, knockout mice also develop gastrointestinal microadenomas with severe dysphasia. The following proposal explores the role of telomerase and telomere length in the maintenance of stem cell compartments in the bone marrow, gastrointestinal tract as and in the lung. In doing so, we will examine the paradox of telomere shortening limiting tissue renewal capacity as well as being a nidus for neoplastic processes. These effects are particularly relevant as telomerase inhibitors are actively pursued as anti-cancer therapies. ? ? ?
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