PROJECT SUMMARY/ABSTRACT:
Telomere homeostasis is critical for cellular replicative capacity and human health. Telomeres shorten with
cellular replication and when critically short, trigger senescence and halt cell division. Inherited mutations in
telomere maintenance genes are associated with severe hematopoietic disorders including childhood-onset
bone marrow failure, aplastic anemia, and myelodysplastic syndrome, as well as non-hematopoietic conditions
including liver cirrhosis and pulmonary fibrosis. These diseases are collectively referred to as telomere biology
disorders (TBDs). Treatment for TBDs is centered on supportive care and bone marrow or organ transplant
which often have poor outcomes and leave patients at risk for other disease manifestations. New approaches to
therapeutically lengthen telomeres and treat TBDs are needed. In order to identify novel pathways controlling
human telomere length, we recently performed a genome-wide CRISPR/Cas9 screen with a telomere length
readout. In addition to identifying known telomere maintenance genes, we identified an association between
several nucleotide metabolism genes and telomere length. Recent human genome wide association studies
have also connected nucleotide metabolism genes and telomere length in blood cells. Preliminary experiments
performed in our laboratory demonstrate that both genetic and small molecule perturbations of nucleotide
metabolism can rapidly and robustly alter telomere length in human cells, including induced pluripotent stem
cells derived from patients with TBDs. However, there are fundamental knowledge gaps both in the mechanisms
underlying this effect, and whether manipulating nucleotide metabolism could alter telomere maintenance in the
hematopoietic system, which could be therapeutically useful. Here, we aim to uncover how nucleotide
metabolism perturbations alter telomere length in human cells, including in vitro and in vivo models of human
hematopoiesis. This study consists of two aims to investigate: (1) how altering nucleotide metabolism genes
impacts telomere maintenance, and (2) how small molecule manipulation of nucleotide metabolism alters
telomere homeostasis, in human cells including primary hematopoietic stem and progenitor cells. For this F30
award, the PI has designed a research strategy and training program that will provide him with: (1) fundamental
expertise in metabolomics, bioinformatics, and telomere biology, (2) an expert group of mentors and
collaborators to promote not only research expertise, but also career-long academic skills including
grantsmanship and scientific communication, and (3) experience performing translation-focused hematology
research in preparation for his career goal as a physician-scientist. This proposal will take place in the rich and
collaborative Harvard Medical School and Boston Children’s Hospital research environments. Completion of this
work is expected to establish nucleotide metabolism as a critical regulator of human telomere homeostasis, with
therapeutic implications for the treatment of hematopoietic diseases with high unmet need including bone marrow
failure and aplastic anemia, as well as other non-hematopoietic degenerative diseases.