Thesis (Ph.D.)--University of Alberta, 2009. / A thesis submitted to the Faculty of Graduate Studies and Research in partial fulfillment of the requirements for the degree of Doctor of Philosophy, Department of Cell Biology. Title from pdf file main screen (viewed on October 18, 2009). Accompanied by four supplementary video recording files. Includes bibliographical references.

Thesis (Ph. D.)--Illinois State University, 1981. / Title from title page screen, viewed March 24, 2005. Dissertation Committee: Arlan Richardson (chair), Herman Brockman, Fritz Schwalm, Harry Huizinga, Tak Cheung. Includes bibliographical references (leaves 81-89) and abstract. Also available in print.

Thesis Ph. D.)(Chemical Engineering)--University of Pretoria, 2003. / Title from opening screen (viewed Oct. 06, 2004). Summaries in English and Afrikaans. Includes bibliographical references (leaves 144-151).

Thesis (M. S.)--Biomedical Engineering, Georgia Institute of Technology, 2008. / Committee Chair: Dr. Athanassios Sambanis; Committee Member: Dr. Barbara Boyan; Committee Member: Dr. Peter Thule.

Thesis (M.S.)--West Virginia University, 2010. / Title from document title page. Document formatted into pages; contains vi, 44 p. : ill. (some col.), map. Includes abstract. Includes bibliographical references (p. 28-35).

No description available.

Hematopoietic stem cells (HSCs) lie at the top of the hematopoietic hierarchy and give rise to all mature blood cells. They are tightly regulated not only by cell-intrinsic but also cell-extrinsic mechanisms that allow HSCs to respond to dynamic physiological demands of the body. HSCs build the hematopoietic system during development and maintain homeostasis in adults by changing their properties according to different needs. A niche is the microenvironment where HSCs reside and receive extrinsic regulation. Understanding the niche is crucial for elucidating how HSCs are regulated by extrinsic cues. During mammalian development, HSCs pass through several different niches, among which the liver is the major site for their rapid expansion and maturation. The fundamental question of what cells constitute the fetal liver niche in vivo remains largely elusive. It is also unclear whether and how cell-extrinsic maintenance mechanisms accompany changes in HSC properties during ontogeny. Here, I genetically dissected the cellular components of the HSC niche in the fetal liver by identifying the cellular source of a key cytokine, stem cell factor (SCF). In addition, I found that HSCs switch to depend on thrombopoietin (TPO), another key factor, during ontogeny and uncovered the mechanism by which HSCs gain this dependence.

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published_or_final_version / Surgery / Doctoral / Doctor of Philosophy

The multidrug resistance associated proteins (MRP(human)Mrp (rat) are ATP-dependent transporters responsible for the efflux of a wide range of substrates, including endogenous compounds e.g. bilirubin, drug metabolites e.g. paracetamol glucuronide and fluorescent dyes e.g. 5 (and 6)-carboxy-2’,7’-dichlorofluorescein (CDF). Mrp1-6 (<i>abccl-6)</i> are expressed in rat liver, with Mrp2 being expressed at the highest level. Isolation of hepatocytes by <i>in situ</i> collagenase perfusion causes bile canalicular disruption and internalisation of Mrp2. Cells cultured in a sandwich configuration of Matrigel or collagen (Type 1) showed bile canalicular reformation at different days in cell culture, depending on the extracellular matrix and time of overlay. We have developed a method for quantifying Mrp-mediated efflux in hepatocytes cultured in a sandwich configuration of collagen (Type 1). This method is unique in its ability to distinguish between sinusoidal efflux, canalicular efflux and diffusion in intact hepatocytes. Alternative <i>in vitro</i> models of Mrp2-mediated efflux include the vesicular (direct and indirect methods) and the ATPase assays. We have used these assays to identify atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin as substrates of human and rat MRP2/Mrp2. A close correlation was seen between the kinetic parameters of transport of the Mrp2 substrate; CDF determined in sandwich cultured rat hepatocytes using the method above (Km = 3.5 – 9.9 μM), vesicle preparations (Km = 37.9 μM) and membrane preparations (Km = 18.7 μM). We also present data to implicate the nuclear receptors, PXR, CAR and FXR in the regulation of <i>abcc2</i> and <i>abcc3</i> and PXR and CAR in <i>abcc1</i> gene regulation. <i>Abcc2 </i>and abcc5<i> </i>are also up-regulated in response to a toxic insult to the cell, probably via Nrf2 activation, suggesting a role in cell defence.