Telomeres are nucleotide specific sequences at the ends of eukaryotic linear chromosomes and are responsible for protecting chromosome termini. Telomeres shorten with mitotic cell division, but are maintained in stem cells by the action of telomerase that enzymatically adds nucleotides to the 3' of the chromosome. Telomerase is constituted by the reverse transcriptase (TERT), a RNA component (TERC), and associated proteins, including dyskerin, encoded by the DKC1 gene. Mutations in these genes can result in human diseases, including aplastic anemia, pulmonary fibrosis, hepatic cirrhosis and dyskeratosis congenita. The generation of induced pluripotent stem (iPS) cells has been used as a model in some human diseases, as reprogramming to the pluripotent state may maintain the initial genotypic characteristics. In our laboratory, together with the NIH, we successfully generated iPS cells from patients with mutations in TERT, TERC, and DKC1 and we observed telomere elongation deficiency during reprogramming. In this project, we plan to promote the differentiation of iPS cells from patients and healthy individuals in different cell types affected (hematopoietic and hepatocytes) or not (neurons) in telomere diseases aiming (1) to characterize the telomere dynamics and telomerase expression during the differentiation process in telomerase-deficient and healthy iPS cells and (2) to determine if the telomerase deficiency modulates the ability of pluripotent cells to differentiate into blood and hepatocytes, which could contribute to the pathophysiology of the disease.
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