Chronic oxidative stress exacerbates an array of erythroid disorders, including hemoglobinopathies, polycythemia vera and anemia of inflammation; yet the mechanisms engaged by erythroid chronic stress- response remain relatively unexplored. In addition, their impact on normal physiological processes is unknown. Our focus has been on the homeostatic transcription factor FOXO3 which is essential for the regulation of the erythropoiesis redox state. We showed recently that FOXO3 is critical for terminal maturation and enucleation in erythropoiesis. On the other hand, our studies indicate that the loss of FOXO3 improves significantly anemia in a model of -thalassemia that is a genetic disorder of erythroid cells with redox imbalance at its core. Given the broad scope of FOXO3 functions, the extent of its impact on erythropoiesis may depend on the context. Our overarching goal is to test the hypothesis that chronic activation of FOXO3-mediated stress-response pathways contributes significantly to the deleterious pathophysiology of erythroid disorders. To test this hypothesis we propose to employ novel quantitative imaging methodologies, genomic high-throughput approaches, and in vitro cultures of human erythroblasts and mouse models generated on pure genetic background combined with loss- and gain-of-function approaches to achieve the following independent yet highly complementary and synergistic aims:
(Aim 1) : To investigate mechanisms whereby FOXO3 regulates erythroblast enucleation;
(Aim 2) : To elucidate the role of FOXO3 in ?-thalassemic erythropoiesis. These combined studies will elucidate how chronic activation FOXO3-mediated stress response may alter normal physiological processes and aggravate ?-thalassemia specifically and more broadly erythroid disorders.
Anemia is a major health problem affecting human populations. Production of red blood cell (RBC) in vitro for clinical use is an achievable goal that is hampered by lack of sufficient knowledge of RBC formation. Studies proposed here are designed to elucidate the function of novel molecules/pathways implicated in RBC formation and their impact on RBC disorders specifically ? thalassemia.
| Liang, Raymond; Ghaffari, Saghi (2018) Stem Cells Seen Through the FOXO Lens: An Evolving Paradigm. Curr Top Dev Biol 127:23-47 |
| Liang, Raymond; Ghaffari, Saghi (2017) Mitochondria and FOXO3 in stem cell homeostasis, a window into hematopoietic stem cell fate determination. J Bioenerg Biomembr 49:343-346 |
