Thesis (Ph.D.)--Victoria University of Wellington, 2008. / Includes bibliographical references.

Thesis (M.S.)--West Virginia University, 2008. / Title from document title page. Document formatted into pages; contains vii, 68 p. : ill. (some col.). Includes abstract. Includes bibliographical references (p. 46-68).

Thesis (Ph. D.)--University of Washington, 1998. / Vita. Includes bibliographical references (leaves [48]-59).

Thesis (M. Med. Sc.)--University of Hong Kong, 2002. / Includes bibliographical references (leaves 53-61).

Thesis (M.Med.Sc.)--University of Hong Kong, 2002. / Includes bibliographical references (leaves 53-61). Also available in print.

Thesis (Ph. D.)--University of Hong Kong, 2005.

Thesis (doctoral)--Katholieke Universiteit te Leuven. / Includes bibliographical references (p. 141-152).

Thesis (M. Med. Sc.)--University of Hong Kong, 2005.

Perinatal inflammation contributes to neurodevelopmental diseases, and animal models have revealed that the inflammatory response within the central nervous system is age dependent. It remains unclear what intrinsic and/or extrinsic factors are responsible for this variation. Here, my aim was to discover the mechanisms responsible for the age-dependent changes in the inflammatory response of the brain by injecting interleukin-1 (IL-1β) into the brain of mice at postnatal day (P)7, P14, P21 or into adult mice. A "window of susceptibility" was found at P14, which was associated with marked neutrophil recruitment and blood-brain barrier (BBB) breakdown, in response to a low dose of IL-1β. Evaluation of cytokine, chemokine, and adhesion molecule mRNA transcripts failed to reveal any specific increases in basal or reactive expression following the injection of IL-1β at P14. The extrinsic hepatic acute phase response (APR) was evaluated, but, once again, there was no evidence that an altered APR might account for the enhanced inflammatory response at P14. Indeed, an inverse relationship between the magnitude of the leukocyte recruitment to the brain and the APR was discovered. Enhancement of the APR with intravenous IL-1β after injection of a low dose of IL-1β into the brain was found to reduce the number of neutrophils and BBB permeability in the brain. While no molecular changes seem to account for the presence of the "window of susceptibility", a population of Iba-1⁺ large, flattened and irregular perivascular cells was discovered within the P14 brain, that may contribute to the increased leukocyte recruitment at P14. Although variations in the brain inflammatory response with development were not fully account for, my results highlight the importance of the systemic inflammatory response on the outcome of acute brain injury and suggest that the systemic APR might be manipulated therapeutically to protect the brain in the perinatal period.

The inherited bone marrow failure syndrome Fanconi Anaemia (FA) is caused by mutations in any one of the multiple FANC genes, which encode proteins that collaborate in the FA/BRCA DNA damage response pathway. FA is characterised by extreme predisposition to acute myeloid leukaemia (AML). AML in FA is associated with typical chromosomal aberrations involving gains of the long arm of chromosome 3 (3q gains). These are linked to overexpression of the oncogene ecotropic viral integration site 1 (EVI1). Based on this clinical observation, the hypothesis that EVI1 confers leukaemic transformation, in particular in the context of FA, was tested. Mouse embryonic stem cells with either functional or disrupted FA/BRCA-pathway were used to model normal and FA-associated embryonic haematopoiesis, and the effect of EVI1 overexpression was assessed in this model. EVI1 functions were also investigated with respect to protein interactions, focusing on the interaction with the co-repressor C-terminal binding protein 1 (CtBP1), in the context of genotoxic stress. To study this, in vitro haematopoietic differentiation assays, flow cytometry, mass spectrometry, immunoprecipitations and immunofluorescence were employed. In vitro haematopoietic differentiation using mouse embryonic stem cells with defective Fanca was successfully developed and applied. The analysis revealed that EVI1 overexpression in haemangioblast-like cells prevented the generation of haematopoietic precursors through endothelial to haematopoietic transition. Studies into EVI1 protein interaction dynamics showed that DNA damage-induced phosphorylation of EVI1 modifies interaction with the co-repressor CtBP1. This interaction was demonstrated to be partially required for the EVI1-induced block of the development of haematopoietic precursors using the mESC-based model. An EVI1-mediated modulation of the FA phenotype characteristic G2-arrest and of the FA-associated embryonic haematopoiesis was not demonstrated. This study contributes to the understanding of the function of the EVI1 oncogene in normal and FA-associated haematopoiesis and the DNA damage response. FA-associated haematopoiesis and leukaemogenesis can be further studied using the embryonic haematopoiesis model developed here, and further studies can build on the data generated with respect to EVI1.