Includes copies of articles co-authored by the author during the preparation of this thesis, in back pocket. / Errata attached to back flyleaf. / Includes bibliographical references (leaves 127-139). / 139 leaves : ill. (some col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / The results presented lend further evidence to previous work suggesting that cold shock domain factors function to repress granulocyte macrophage-colony stimulating factor transcription via DNA binding to single stranded regions across the proximal promoter. / Thesis (Ph.D.)--Adelaide University, Dept. of Medicine, 2001

Thesis (Ph. D.)--University of Wisconsin--Madison, 1969. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Call number: LD2668 .T4 1984 G58 / Master of Science

Normal tissue homeostasis and appropriate responses to injury and infection are dependent on cellular communication mediated by cell surface receptors that respond to extrinsic stimuli. The GM-CSF receptor was the major focus of this project. This receptor shares a common signalling subunit, β [subscript c], with the IL-3 and IL-5 receptors. The unique GM-CSF receptor α-subunit ( GMRα ) confers ligand binding specificity to the complex and is essential for GM-CSF receptor signalling, although the full complement of signalling events mediated by GMRα remains elusive. Through cloning of candidate interacting proteins, expression and co-immunoprecipitation studies, we have confirmed interactions for two proteins previously reported to interact with the GMRα, p85 and IKKβ. Additionally, we identified the Src family kinase, Lyn, as a novel direct interacting partner of GMRα and provide insights into possible roles of this kinase in initiating signalling from the GM-CSF receptor. In addition to GMRα associated events we aimed to further characterise the role of the common β [subscript c] subunit in GM-CSF mediated signalling. We utilised two classes of consitutively active β [subscript c] mutants ( extracellular or transmembrane ) which transform the bi-potential myeloid FDB1 cell line to either factor-independent growth and survival, or granulocyte-macrophage differentiation, respectively. Here we report a comprehensive biochemical analysis of signalling by these two classes of mutants in this cell line. The two activated GMR mutants displayed distinct and non-overlapping signalling capacity. In particular, expression of a mutant with a substitution in the transmembrane domain ( V449E ) selectively activated JAK / STAT5 and MAPK pathways resulting in a high level of sensitivity to JAK and MEK inhibitors. In contrast, expression of a mutant with a 37 amino acid duplication in its extracellular domain ( FI Δ ) selectively activates the PI3K / AKT and IKKβ / NFkB pathways. Cells responding to this mutant display a relative high level of sensitivity to two independent PI3K inhibitors and relative resistance to inhibition of MEK and JAK2. The non-overlapping nature of signalling by these two activated mutants suggests that there are alternative modes of receptor activation that differentially dependent on JAK2 and that act synergistically in the mature liganded cytokine receptor complex. Further detailed analysis of these mutants will facilitate the dissection of the signalling pathways involved in the GM-CSF response that mediate proliferation, survival and differentiation. / Thesis (Ph.D.)--School of Medicine, 2007.

In the ewe, one to three antral follicles emerge or grow from a pool of small antral follicles (1 to 3 mm in diameter) every 3 to 5 days and reach diameters of ¡Ý5 mm before regression or ovulation. Each follicular wave is triggered by a peak in serum concentrations of FSH. It is not clear what characteristics of an FSH peak cause follicular wave emergence and what aspects of development of a follicular wave are regulated by its preceding FSH peak.<p> In Experiment 1, we found that the amplitude of FSH peaks decreased, while basal serum FSH concentrations increased across the inter-ovulatory interval (P < 0.05). However, there were no associated changes in the growth, static or regression phases of follicular waves or the number and size of follicles in a wave. In Experiment 2, using computer-assisted quantitative echotextural analysis, we found that the numerical pixel value (NPV) for the wall of anovulatory follicles emerging in the third wave of the cycle was significantly higher than for waves 1 and 2 at the time of wave emergence but it decreased as follicles reached maximum follicular diameter (P < 0.05). A tendency for a similar pattern for the wall of follicles in the last wave of the cycle was also observed (P = 0.07).<p> In Experiment 3, treatment with ovine FSH (oFSH) increased the amplitude of an FSH peak by 5 to 6 fold. This treatment increased estradiol production (P < 0.05) but had little effect on other characteristics of the subsequent follicular wave. Daily injections of oFSH (Experiment 4) for four days, resulted in the occurrence of 4 discrete peaks in serum FSH concentrations. Each injection of oFSH resulted in the emergence of a new follicular wave.<p> In Experiment 5, six cyclic ewes received oFSH (0.1 ¦Ìg/kg, sc) every 6 h for 42 h, to try to give a gradual increase in the leading slope of an FSH peak. Serum FSH concentrations increased in oFSH treated ewes (P < 0.05) resulting in an additional peak between two endogenously driven FSH peaks and therefore, did not give the planned gradual leading slope to an FSH peak. Ovine FSH treatment occurred in the early growth phase of wave 1 of the inter-ovulatory interval and increased the growth rate of growing follicles in that wave, compared to control ewes (P < 0.05). This apparently induced dominance in follicles in wave 1, causing them to suppress wave emergence in response to the injected FSH. In Experiment 6, oFSH was infused constantly (1.98 ¦Ìg/ewe/h, iv, n = 6) for 60 h. Infusion of oFSH maintained serum FSH concentrations at a level similar to the zenith of a peak. This resulted in a superstimulatory effect with a peak in the mean number of large follicles on Day 2 after the start of FSH infusion (P < 0.001).<p> A hormonal milieu similar to low serum progesterone concentrations was created by treatment of ewes with prostaglandin and medroxyprogesterone acetate (MAP) sponges (Experiment 7). This treatment delayed regression of the penultimate follicular wave of a cycle. However, the delayed follicular atresia was accompanied by a greater degree of apoptosis in somatic cells of follicles growing in the penultimate wave compared to those in the final wave of the cycle, when collected one day before expected ovulation.<p> In conclusion, trends in basal serum concentrations of FSH and peaks in serum FSH concentrations, across the estrous cycle, are associated with changes in the image attributes of follicles emerging later in the estrous cycle, perhaps reflecting a greater readiness of those follicles for ovulation and formation of CL. The ovine ovary can respond to discrete peaks in serum FSH concentrations with the emergence of new follicular waves on a daily basis. This led us to conclude that follicular dominance is not evident in the ewe and peaks in serum FSH concentrations are likely to be driven by some endogenous rhythm that is unrelated to ovarian follicular secretory products. However, direct dominance can be induced by giving supplemented FSH during the growth phase of a follicle. Extended exposure of ovine ovaries to the serum concentrations of FSH found at the zenith of a peak overrides the mechanisms that recruit follicles into a wave and induces a superovulatory response in cyclic ewes. Finally, an increase in the incidence of apoptosis occurs in antral follicles in sheep that have an extended lifespan, prior to any morphological changes detectable by ultrasonography. This would seem to cause decreased follicular viability and lowered fertility of the oocytes that the follicles contain.

In the ewe, one to three antral follicles emerge or grow from a pool of small antral follicles (1 to 3 mm in diameter) every 3 to 5 days and reach diameters of ¡Ý5 mm before regression or ovulation. Each follicular wave is triggered by a peak in serum concentrations of FSH. It is not clear what characteristics of an FSH peak cause follicular wave emergence and what aspects of development of a follicular wave are regulated by its preceding FSH peak.<p> In Experiment 1, we found that the amplitude of FSH peaks decreased, while basal serum FSH concentrations increased across the inter-ovulatory interval (P < 0.05). However, there were no associated changes in the growth, static or regression phases of follicular waves or the number and size of follicles in a wave. In Experiment 2, using computer-assisted quantitative echotextural analysis, we found that the numerical pixel value (NPV) for the wall of anovulatory follicles emerging in the third wave of the cycle was significantly higher than for waves 1 and 2 at the time of wave emergence but it decreased as follicles reached maximum follicular diameter (P < 0.05). A tendency for a similar pattern for the wall of follicles in the last wave of the cycle was also observed (P = 0.07).<p> In Experiment 3, treatment with ovine FSH (oFSH) increased the amplitude of an FSH peak by 5 to 6 fold. This treatment increased estradiol production (P < 0.05) but had little effect on other characteristics of the subsequent follicular wave. Daily injections of oFSH (Experiment 4) for four days, resulted in the occurrence of 4 discrete peaks in serum FSH concentrations. Each injection of oFSH resulted in the emergence of a new follicular wave.<p> In Experiment 5, six cyclic ewes received oFSH (0.1 ¦Ìg/kg, sc) every 6 h for 42 h, to try to give a gradual increase in the leading slope of an FSH peak. Serum FSH concentrations increased in oFSH treated ewes (P < 0.05) resulting in an additional peak between two endogenously driven FSH peaks and therefore, did not give the planned gradual leading slope to an FSH peak. Ovine FSH treatment occurred in the early growth phase of wave 1 of the inter-ovulatory interval and increased the growth rate of growing follicles in that wave, compared to control ewes (P < 0.05). This apparently induced dominance in follicles in wave 1, causing them to suppress wave emergence in response to the injected FSH. In Experiment 6, oFSH was infused constantly (1.98 ¦Ìg/ewe/h, iv, n = 6) for 60 h. Infusion of oFSH maintained serum FSH concentrations at a level similar to the zenith of a peak. This resulted in a superstimulatory effect with a peak in the mean number of large follicles on Day 2 after the start of FSH infusion (P < 0.001).<p> A hormonal milieu similar to low serum progesterone concentrations was created by treatment of ewes with prostaglandin and medroxyprogesterone acetate (MAP) sponges (Experiment 7). This treatment delayed regression of the penultimate follicular wave of a cycle. However, the delayed follicular atresia was accompanied by a greater degree of apoptosis in somatic cells of follicles growing in the penultimate wave compared to those in the final wave of the cycle, when collected one day before expected ovulation.<p> In conclusion, trends in basal serum concentrations of FSH and peaks in serum FSH concentrations, across the estrous cycle, are associated with changes in the image attributes of follicles emerging later in the estrous cycle, perhaps reflecting a greater readiness of those follicles for ovulation and formation of CL. The ovine ovary can respond to discrete peaks in serum FSH concentrations with the emergence of new follicular waves on a daily basis. This led us to conclude that follicular dominance is not evident in the ewe and peaks in serum FSH concentrations are likely to be driven by some endogenous rhythm that is unrelated to ovarian follicular secretory products. However, direct dominance can be induced by giving supplemented FSH during the growth phase of a follicle. Extended exposure of ovine ovaries to the serum concentrations of FSH found at the zenith of a peak overrides the mechanisms that recruit follicles into a wave and induces a superovulatory response in cyclic ewes. Finally, an increase in the incidence of apoptosis occurs in antral follicles in sheep that have an extended lifespan, prior to any morphological changes detectable by ultrasonography. This would seem to cause decreased follicular viability and lowered fertility of the oocytes that the follicles contain.

No description available.

Thesis (Ph.D.) -- University of Adelaide, Dept. of Obstetrics and Gynaecology, 1999. / Errata posted inside back end-paper (leaf 250). Bibliography: leaves 204-249.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1957. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 214-215).

Thesis (Ph. D.)--University of Wisconsin--Madison, 1981. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 125-131).