Errata inserted. / Includes bibliographical references. / xi, 119, [75] leaves, [21] leaves of plates : ill. (chiefly col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / This study demonstrates a conserved structural organisation of the mouse LIF gene that produces three differentially localised proteins. This provides a mechanism for specific control of the sites of LIF action and mechanisms for mediating the variety of putative actions for the LIF gene. Intracellular localisation of the LIF protein provides another example of intracellular cytokine action, mediated by a novel mechanism and provides a system for separate analysis of intracellular and extracellular cytokines. / Thesis (Ph.D.)--University of Adelaide, Dept. of Biochemistry,1998?

Errata inserted. / Includes bibliographical references. / xi, 119, [75] leaves, [21] leaves of plates : ill. (chiefly col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / This study demonstrates a conserved structural organisation of the mouse LIF gene that produces three differentially localised proteins. This provides a mechanism for specific control of the sites of LIF action and mechanisms for mediating the variety of putative actions for the LIF gene. Intracellular localisation of the LIF protein provides another example of intracellular cytokine action, mediated by a novel mechanism and provides a system for separate analysis of intracellular and extracellular cytokines. / Thesis (Ph.D.)--University of Adelaide, Dept. of Biochemistry,1998?

Thesis (Ph. D.)--University of Adelaide, Dept. of Biochemistry, 1998? / Errata inserted. Includes bibliographical references.

Addendum attached to back facing leaves. Includes bibliographical references (leaves 172-199). The findings establish leukemia inhibitory factor, and possibly oncostatin M, as new members of a small but growing class of cytokines produced in an intracellularly active form and also suggest that the production of alternate transcripts and intercellularly-retained proteins may be a common and important feature of cytokines of the IL-6 and other families.

Addendum attached to back facing leaves. / Includes bibliographical references (leaves 172-199). / 199 leaves, 5 photographic plates : ill. (some col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / The findings establish leukemia inhibitory factor, and possibly oncostatin M, as new members of a small but growing class of cytokines produced in an intracellularly active form and also suggest that the production of alternate transcripts and intercellularly-retained proteins may be a common and important feature of cytokines of the IL-6 and other families. / Thesis (Ph.D.)--University of Adelaide, Dept. of Biochemistry, 2000

Thesis (Ph.D.) -- University of Adelaide, Dept. of Biochemistry, 2000. / Addendum attached to back facing leaves. Includes bibliographical references (leaves 172-199).

<p>About 30 % of all infertile couples suffer from infertility of an unexplained cause. Leukemia inhibitory factor (LIF) is a glycoprotein produced by the endometrium and is an important cytokine in the implantation process. LIF exerts its biological functions through heterodimerization of its two receptors: LIF receptor (LIFR) and gp130. Point mutations in the LIF gene have been associated with female infertility. The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) in the genes of LIFR and gp130 could cause reduced fertility in women. To this end, 115 samples from women diagnosed with unexplained infertility and 191 samples from fertile women were studied. Three SNPs in the gp130 gene and two SNPs in the LIFR gene were analyzed using real-time PCR. One significant difference and a tendency to difference were detected in the gp130 gene for women with unexplained infertility. There were no differences in the LIFR gene variations. In conclusion, polymorphisms in gp130, and thereby disturbances in the LIF pathway, could be one cause for infertility in women diagnosed with unexplained infertility.</p>

About 30 % of all infertile couples suffer from infertility of an unexplained cause. Leukemia inhibitory factor (LIF) is a glycoprotein produced by the endometrium and is an important cytokine in the implantation process. LIF exerts its biological functions through heterodimerization of its two receptors: LIF receptor (LIFR) and gp130. Point mutations in the LIF gene have been associated with female infertility. The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) in the genes of LIFR and gp130 could cause reduced fertility in women. To this end, 115 samples from women diagnosed with unexplained infertility and 191 samples from fertile women were studied. Three SNPs in the gp130 gene and two SNPs in the LIFR gene were analyzed using real-time PCR. One significant difference and a tendency to difference were detected in the gp130 gene for women with unexplained infertility. There were no differences in the LIFR gene variations. In conclusion, polymorphisms in gp130, and thereby disturbances in the LIF pathway, could be one cause for infertility in women diagnosed with unexplained infertility.

Thesis (Ph. D.)--Hong Kong University of Science and Technology, 2004. / Includes bibliographical references (leaves 134-172). Also available in electronic version. Access restricted to campus users.

The mammalian testis is divided into two distinct compartments which carry out its principal functions. Spermatogenesis occurs within the seminiferous tubules and androgen biosynthesis primarily occurs in the interstitial space. Both these processes are entirely dependent upon the two major testicular somatic cell populations - the Sertoli and Leydig cells respectively. In human males, testicular spermatogenic and endocrine function declines during the ageing process. Of particular significance is the reported age-related decrease in Leydig cell androgen production as androgens have been suggested to play a crucial role in supporting lifelong general health in men, with low circulating testosterone linked to an increased risk of developing chronic age-related cardiometabolic diseases. However, the relationship between ageing, testicular function and disease is not fully understood, impeding the development of novel therapeutic strategies to treat age-related testicular dysfunction. In one set of studies undertaken herein, a series of novel mouse models of premature ageing were utilised to begin to dissect the process of age-related testicular degeneration. Firstly, a novel knockout-first conditional allele of a previously reported premature-ageing model driven by Cisd2 (CDGSH Iron Sulphur Domain 2) deficiency was validated and the testicular phenotype characterised and compared to that of naturally aged mice at 18-months of age. Histological analyses revealed premature testicular atrophy at 6-months of age in CISD2 deficient mice, consistent with observations of the naturally aged testis. Circulating testosterone was significantly lower in CISD2-deficient mice compared to wild-type controls at 6-months of age and the luteinising hormone/testosterone ratio was significantly elevated, indicative of compensated Leydig cell failure. mRNA expression of key genes involved in androgen production were also significantly reduced in the CISD2-deficient testis, pointing to Leydig cell dysfunction in this model of premature aging. Next, Cre/LoxP technology was used to delete Cisd2 from specific testicular cell populations to determine which cell types control/support Leydig cell function during the ageing process. Testosterone production was unaffected when Cisd2 was disrupted in either the Leydig cell population or Sertoli cell population. These observations suggest that disruption to the testicular microenvironment in which Leydig cells reside, rather than intrinsic Leydig cell ageing, may play a significant role in age-associated Leydig cell dysfunction. A second set of studies were carried out to investigate the role of leukemia inhibitory factor (LIF) signalling in the maintenance of testicular function. LIF is a pleiotropic cytokine belonging to the interleukin-6 family. In the rodent testis, LIF is expressed in fetal life and adulthood; the peritubular myoid cells thought to be the main site of production. Given their anatomical location within the testis, LIF produced by peritubular myoid cells may act on both intratubular and interstitial cells to influence spermatogenesis and steroidogenesis respectively. Indeed, LIFR is expressed in germ cells, Sertoli cells, Leydig cells as well as testicular macrophages suggesting that LIF may be a key paracrine regulator of testicular function. However, the precise role of LIF/LIFR signalling in the testis is largely unknown. As such, models of testicular cell-specific Lifr deletion were generated using Cre/LoxP technology. Analysis of these novel models of conditional LIFR ablation revealed that LIFR is dispensable in germ cells for normal spermatogenesis. However, LIFR ablation from Sertoli cells resulted in a progressive degenerative phenotype, characterised by abnormal germ cell loss, sperm stasis, seminiferous tubule distention and subsequent atrophy of the seminiferous tubules. In a final set of studies, a rat model of Leydig cell ablation-regeneration was used to determine the regenerative capacity of human adipose-derived perivascular stem cells (hAd-PSC) as a potential therapy for testicular dysfunction. Following ethane dimethanesulphonate (EDS) mediated Leydig cell ablation, primary hAd-PSCs, cultured with or without LH, IGF-1, PDGFBB, T3 and ITS supplement, were transplanted into the rat testis and Leydig cell regeneration was monitored via serial measurements of circulating luteinising hormone (LH) and testosterone. Overall, hAd- PSCs had no impact on the recovery of circulating testosterone levels. However, when pre-cultured with the cocktail of hormone/growth factor supplements, the LH spike induced by the removal of testosterone negative feedback was dampened, suggesting the transplanted cells may promote Leydig cell regeneration. Whether these cells differentiate into Leydig cells, or simply provide paracrine support to the regenerating Leydig cells remains to be determined. Although Ad-PSCs may enhance regeneration kinetics, the transplanted cells were undetectable in the testis 5 weeks post transplantation suggesting they may not survive in the context of long term xenogeneic transplantation.