published_or_final_version / Physiology / Doctoral / Doctor of Philosophy

published_or_final_version / Physiology / Doctoral / Doctor of Philosophy

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A thesis submitted to the Faculty of Medicine University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Doctor of Philosophy. / In the past 25 years, a large volume of data was collected on steroid hormone receptors and their role in the action mechanisms of steroid hormones. Efforts were made to use the principles, derived from fundamental investigations into the actual function of steroid hormone receptors in target tissues, (e.g. breast and uterine tissues) to provide a comprehensive understanding of the nature of hormone responsive tumours (e.g. breast tumours) and to formulate successful endocrine treatment regimes for e.g. breast cancer patients. Although some measure of success was achieved with antihormonal drugs like tamoxifen, clomiphene, medroxyprogesterone acetate, etc. a statistical analysis of patient response data has revealed disappointingly low median response times for breast cancer patients. A number of reasons can be offered in explanation of the discrepancies between theory and practice, however, it was felt that the two most obvious ones are the lack of a proper animal model, closer to man on the species scale, and insufficient understanding of the actual in vivo mechanisms of steroid hormone action. For this very reason it was decided to launch an in depth investigation into the properties and functions of steroid hormone receptors in the biological action of steroid hormones, especially the sex steroid hormone receptors, like the oestrogen and progesterone receptors. Furthermore, it was decided to employ a nonhuman primate, Cercopithecus aethiops pygerythrus, commonly called the Vervet monkey, as the animal model, instead of the more common Sprague-Dawley rat. Since the field of investigation defined is both broad and deep, it is obvious that this thesis could not contain all the answers. So, in view of the obvious limitation in time and man-power, the prime object for this thesis was defined as the laying of sound foundations for future research on the topic specified above. Thus, it was decided to concentrate on the molecular properties of the uterine oestrogen and progesterone receptors of the Vervet monkey. The basic arsenal of biochemical technology used in protein chemistry (competitive protein binding assays, sucrose density gradient analysis, size exclusion chromatography, ion exchange chromatography, chromatofocussing, isoelectric focussing) and available in the Institute of Life Sciences, Faculty of Medicine, University of Pretoria at the time of this investigation, was employed. In view of the information generated in the course of the study, attention was focussed upon a small, but important aspect of the mechanism of steroid hormone action, namely the process of activation or tranformation of receptor- ligand complexes and their interaction with the nuclear compartment. Since disturbance(s) in these processes in abnormal uterine tissues may exist, a limited study of the oestrogen and progesterone receptors in human uterine tissues was undertaken, because no abnormal Vervet monkey uterine tissues were available. Unfortunately it was also extremely difficult to obtain an abundance of pathological human uterine tissues necessary for an adequate study. The investigator consequently had to be content to study only a small number of pathological uterine specimens. Thus the latter part of this thesis only skims the surface of what could have been a major fait accompli with possible clinical significance. / WHSLYP2017

by Yueming Qian. / Publication date from spine. / Thesis (Ph.D.)--Chinese University of Hong Kong, 1995. / Includes bibliographical references (leaves 209-244). / ABSTRACT --- p.i / ACKNOWLEDGEMENTS --- p.iii / PUBLICATIONS --- p.iv / Chapter CHAPTER 1 --- General Introduction --- p.1 / Chapter CHAPTER 2 --- Methodology --- p.53 / Chapter CHAPTER 3 --- Characterisation of Vascular EP-Receptors --- p.76 / Chapter PART 1 --- EP-receptors on the human isolated pulmonary artery --- p.77 / Chapter PART 2 --- EP-receptors on the guinea-pig isolated aorta --- p.100 / Chapter CHAPTER 4 --- Neuronal IP-Receptors in the Rat Colon --- p.130 / Chapter CHAPTER 5 --- Differential Effects of Non-Prostanoid Prostacyclin Mimetics on Human Pulmonary Artery and Rat Colon --- p.173 / Chapter CHAPTER 6 --- General Discussion and Perspective --- p.200 / REFERENCES --- p.209

The gonadal steroids, testosterone and estradiol, are known to be important modulators of neuronal functions and behaviors in most vertebrate species. These steroid hormones also elicit changes in neuropeptide synthesis and secretion, alter specific neurohormone receptor levels, and alter neuronal morphology and electrophysiology. Many of the actions of androgens and estrogen are mediated by specific intracellular receptors found in certain regions of the brain. But where are these neuronal targets for androgens and estrogen found? The research in this thesis investigates the neuroanatomical distribution of androgen and estrogen receptors in the brain of a urodele amphibian, the roughskin newt, Taricha granulosa. Using immunocytochemistry with antibodies against these receptors, the distribution of both androgen and estrogen receptor-immunoreactive cells is described in the brain of this species. This study found brain regions that contain immunoreactive androgen receptors that have not previously been reported in poikilothermic vertebrates using other techniques. In addition, the distribution of estrogen receptor-immunoreactive cells in most brain areas, and the distribution of androgen receptor-immunoreactive cells in several brain areas, were found to be similar in this amphibian to those described in studies that employed in vivo autoradiographic techniques in other vertebrate species. This study suggests that the neuroanatomical distribution of gonadal steroid receptors is a relatively conserved trait in vertebrates. The widespread distribution of these receptors in the brain probably reflects the multiple functions that androgens and estrogen are known to have in the brain. / Graduation date: 1995

EphrinB ligands and their Eph receptor tyrosine kinases are known to regulate excitatory synaptic functions in the hippocampus. In the CA3-CA1 synapse, ephrinB ligands are localized to the post-synaptic membrane, while their cognate Eph receptors can be expressed in both pre-and post-synaptic membranes. Previous studies show that interaction of ephrinB molecules with Eph receptors leads to changes in long-term potentiation (LTP), suggesting that reverse signaling through postsynaptic ephrinBs may be required for learning and memory. Our collaborative studies demonstrate that the cytoplasmic domain of ephrinB3, and hence reverse signaling, is not required for ephrinB-dependent learning and memory tasks or for LTP of these synapses. We demonstrate that ephrinB3 null mutants show changes in several synaptic proteins including reduced levels of NMDA receptor subunits. These abnormalities are not observed in ephrinB3lacZ reverse signaling mutants, supporting an Eph receptor forward signaling role for ephrinB3 in these processes. NMDA receptors are important in regulating synaptic functions and plasticity in the adult hippocampus, and Eph receptors have been shown to cluster NMDA receptors to the cell membrane. These studies show that ephrinB3 interacts with EphA4 to regulate plasma membrane levels of NR1 in Cos-1 cells and primary hippocampal neurons. In the absence of ephrinB3, NR1 levels are decreased in synaptosomal membranes, increased in microsomal tissues, but not changed in total extracts. This suggests that ephrinB3 regulates NR1 levels through protein trafficking and not gene transcription. Analysis of protein trafficking confirmed that ephrinB3 specifically interacts with EphA4 receptor to regulate NR1 exocytosis but not endocytosis in both transfected Cos-1 cells and primary hippocampal neurons. We postulate that ephrin-Eph receptor interactions are important mediators of synaptic formation and function, in part, through their regulation of NMDA receptors in the hippocampal synapse. In addition, we find that both ephrinB3KO and ephrinB3lacZ mice show an increased number of excitatory synapses, demonstrating a cytoplasmic-dependent reverse signaling role of ephrinB3 in regulating synapse number. Together, these data suggest that ephrinB3 may act like a receptor to transduce reverse signals to regulate the number of synapses formed in the hippocampus, and that it likely acts to stimulate forward signaling through Eph receptors to modulate NMDA receptor trafficking, LTP and learning.

Thesis (Ph. D.)--University of Missouri--Columbia, 2000. / Typescript. Vita. Includes bibliographical references (leaves 113-122). Also available on the Internet.

Thesis (Ph. D.)--University of Washington, 2001. / Vita. Includes bibliographical references (leaves 101-109).