The overarching goal of our laboratory is to delineate the processes that regulate tissue proliferation and differentiation, and how dysregulation of these pathways contributes to human diseases. Our studies utilize erythroid cells as a model system.
Enucleated red blood cells constitute 80% of cells in the body. A precise balance between self-renewal divisions and terminal differentiation is essential for maintaining this enormous pool of cells. Terminal erythroid differentiation is particularly unique in that the differentiation program is coupled to 3-4 rapid terminal cell divisions with peculiarly short G1 phase and fast DNA replication compared to self-renewal divisions. We do not yet understand the processes that regulate the timing, integrity, and the numbers of these rapid terminal divisions. Dysregulation of these terminal divisions leads to impairment of terminal erythroid differentiation and diseases such as Congenital Dyserythropoietic Anemia (CDA), a severe anemia characterized by increased proportions of binucleated erythrocytes.
Our research goals are twofold: 1) Understand how the specialized transcriptional regulation in erythroid cells ensures that the cell cycle machinery is able to accommodate the rapid pace of the terminal cell divisions. Specifically, our lab will investigate how ubiquitous factors regulating DNA replication, centromere cohesion, and cytokinesis, cater to the specialized demands of the rapid erythroid cell divisions. 2) Investigate the molecular pathogenesis of CDA IV, which is a severe anemia caused by a hypomorphic mutation in EKLF/KLF1 (a master regulator of erythropoiesis), that arises due to a failure in terminal cell divisions and result in binucleate erythroblasts and erythroblasts with DNA bridges.
Fruther, we are interested in understanding the mechanisms of hemoglobin switching. An attractive therapeutic strategy to ameliorate and potentially cure beta thalassemia and sickle cell anemia is to manipulate the globin gene regulation by exploiting the biology behind hemoglobin switching. One of our goals is to identify factors that induce fetal hemoglobin in adult erythroid cells due to its ameliorating effects in these anemias.
Our external funding sources are NIDDK/NIH (R01, K01 awards) and Cooley's Anemia Foundation.