@phdthesis{e2aab7b093cc4d378901d10b652f3f80,
title = "Elucidating regulators of red blood cell development in health and disease",
abstract = "Red blood cells are are plentiful, flexible and essential. They are the most abundant cell in our body and their mainobject is to carry oxygen, which is essential for cellular respiration. The formation of red blood cells is callederythropoiesis. Erythropoiesis is intimately coupled to cell division and mitochondrial function. Aberrations in thesetwo processes are often associated with red blood cell disorders, which result in anemia. Anemia is characterizedby the lack of red blood cells and/or reduced hemoglobin concentrations resulting in reduced oxygen transport tothe tissue and inevitable to reduced quality of life and increased mortality. My aim in this thesis has been todeepen our understanding of how erythropoiesis is regulated in health and diseaseIn the first paper we demonstrated that anemia caused by pRb deficiency was due to disrupted differentiation withunderlying impairment to mitochondrial function at the orthochromatic erythroblast stage. The MDS-like phenotypeof pRb deficient mice could be rescued by enhanced PPAR pathway signaling, an important signaling axis inmitochondrial biogenesis, in vivo either genetically or therapeutically.In the second paper we translated our findings in the mouse to a human setting by inhibiting PPAR signaling. Wedemonstrated that perturbed PPAR signaling in human hematopoietic stem/progenitor cells from both bonemarrow and cord blood results in impaired formation of early erythroid progenitors and delayed terminal erythroiddifferentiation in vitro. We showed that PPAR signaling is important for iron, heme and globin homeostasis.Furthermore we demonstrated that PPAR signaling affects cell cycle exit indicating that there is a mutualregulation between cell cycle progression and mitochondrial function during terminal erythropoiesis.In the third paper we demonstrated that Ypel4, which is highly expressed in orthochromatic erythroblasts, isimportant for the integrity of red blood cell membrane. Ypel4 null erythroblast had reduced deformability and werecleared at an increased rate. The phenotype resembled defects normally observed in human hereditarymembrane disorders.Overall the papers included in this thesis highlight mechanisms and genes important for terminal erythropoiesisspecifically in the orthochromatic erythroblast. We further described disease associated with the differentperturbations to erythropoiesis. The work presented",
author = "Taha Sen",
note = "Defence details Date: 2021-11-17 Time: 13:00 Place: BMC I1345, S{\"o}lvegatan 17 i Lund. Join by Zoom: https://lu-se.zoom.us/j/63884757012 External reviewer(s) Name: Palis, James Title: Professor Affiliation: University of Rochester Medical Center, Rochester, NY, USA ",
year = "2021",
language = "English",
isbn = "978-91-8021-128-4",
series = "Lund University, Faculty of Medicine Doctoral Dissertation Series",
publisher = "Lund University, Faculty of Medicine",
number = "2021:121",
type = "Doctoral Thesis (compilation)",
school = "Department of Laboratory Medicine",
}