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http://hdl.handle.net/11375/25211
Title: | Functional characterization of asymmetric cell division associated genes in hematopoietic stem cells and bone marrow failure syndromes |
Authors: | Chan, Derek |
Advisor: | Hope, Kristin |
Department: | Biochemistry and Biomedical Sciences |
Keywords: | Hematopoietic stem cell;Bone marrow failure;Asymmetric cell division;Arhgef2;Staufen1;Shwachman-Diamond syndrome;Aplastic anemia;Paroxysmal nocturnal hemoglobinuria;RNA-binding protein |
Publication Date: | 2020 |
Abstract: | Hematopoietic stem cells (HSCs) are critical to the development of the hematopoietic system during ontogeny and maintaining hematopoiesis under steady-state. Several genes implicated in asymmetric cell division (ACD) have been found to influence HSC self-renewal in normal hematopoiesis and various leukemias. From a separate survey of genes associated with ACD, I now present the results from dedicated functional studies on two genes – Arhgef2 and Staufen1 – in HSCs and identify their potential contributions to benign hematopoietic disorders. Specifically, I present evidence that demonstrates a conserved role of Arhgef2 in orienting HSC division, the loss of which leads to HSC exhaustion that may underlie and contribute to the pathogenesis of Shwachman-Diamond syndrome. I also identify Staufen1 as a critical RNA-binding protein (RBP) in HSC function, downregulation of which elicits expression signatures consistent with clinical anemias reminiscent of aplastic anemia and/or paroxysmal nocturnal hemoglobinuria. I end by reviewing how RBPs function in HSCs and discuss future research directions that could further elucidate how bone marrow failure syndromes arise at the stem cell level. |
URI: | http://hdl.handle.net/11375/25211 |
Appears in Collections: | Open Access Dissertations and Theses |
Files in This Item:
File | Description | Size | Format | |
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Chan_Derek_CH_2019December_PhD.pdf | 9.76 MB | Adobe PDF | View/Open |
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