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Inez Czerwionka - MSc
Role of Inhibitor of Apoptosis Protein (IAP) in malignant mesothelioma
Apoptosis is a mode of physiological cell death that permits the selective removal of a discrete population of cells in the absence of an immune response or inflammatory reaction. Apoptosis plays role in many physiological and pathological processes such as homeostatic control, tissue remodeling and cellular replacement. The processes of apoptosis are complex and multi-factorial. The elucidation of specific apoptotic signals and pathways may hold the key to potential therapies in the cure and prevention of neoplasia. My aim is to characterize the potential anti-apoptotic role of inhibitor of apoptosis protein (IAP) primarily in mammary, prostate tissues and mesothelioma.
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Lloyd White - B.Sc (Hons)
Role of Secreted Frizzled-Related Protein (sFRP-4) in keratinocyte apoptosis
My study deals with roles for the glycoprotein sFRP-4 (secreted Frizzled-related protein 4) in regulating differentiation-induced apoptosis or programmed cell death (PCD) in keratinocytes. Secreted FRP proteins are generally known to modulate Wnt ligand and Frizzled receptor protein-protein interactions. This complex Wnt signaling pathway is involved in regulating the growth and differentiation of epithelia associated with most human organ systems. We propose to study sFRP-4 functions in keratinocytes comprising the epidermis, the self-renewing epithelial component of skin. Epidermal stem cells give rise to keratinocytes, which progress outward as they terminally differentiate and ultimately form anucleated squames in the outermost skin layers. This specialized form of PCD allows for loss of aged and/or damaged epidermal cells and is essential for cornification and competent barrier functions of the epidermis.
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Melissa Berg - BSc (Hons)
Steroid Regulation of Apoptosis in Rat Mammary Gland
The mammary gland, after substantial proliferation during pregnancy, involutes via the mechanism of apoptosis at the time of weaning. My honours project found that glucocorticoids and progesterone, normally present during lactation, prevented apoptosis in the mammary gland and thus, apoptosis was induced during lactation when these steroids were removed. To extend these findings, my PhD will delineate the specific molecular pathways by which progesterone and glucocorticoids prevent apoptosis in the lactating mammary gland. In particular, I will examine the possibility that these anti-apoptotic effects of glucocorticoids and progesterone are mediated via the same receptor, and involve interaction with other transcription factors.
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Jeremy Drake - BSc (Hons)
Y81 in Ovarian Cancer
My honours thesis examined the role of Y81 gene in the rat ovary during ovulation and its association with apoptosis, a form of physiological cell death. The expression of Y81 in hormone dependent tissues is known to inhibit a specific signaling pathway for cellular growth and differentiation. Pro-apoptotic genes are down regulated in tumour cells, allowing them to proliferate. The pro-apoptotic gene Y81 is widely expressed in normal ovarian tissue but is not expressed in ovarian tumour cells. During my PhD I plan to investigate the regulation of genes, particularly Y81, in ovarian cancer compared to normal tissue and to manipulate the expression of these genes in cancer cells to better understand their function.
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Matthew Dalrymple - BSc (Hons)
Molecular basis of GPCR signaling and trafficking pathways that are involved in both reproductive events and obesity.
Hypothalamic neuropeptides and G-protein coupled receptors (GPCRs) are a major new frontier for drug development in the treatment of a broad spectrum of diseases. An important advantage of GPCR's, unlike other families of membrane bound receptors, is that they are ready targets for the development of orally active non-peptide molecules. The hypothalamic-pituitary gonadal axis controls and regulates gonadal function so it is a primary target for investigation into novel methods of controlling reproduction and for the treatment of steroid-dependent cancers. GnRH, the central regulator of reproductive function, is released in a pulsatile fashion from the hypothalamus and acts upon the gonadotrope. The human GnRH receptor is an extremely important focus in drug discovery programs due to its pivotal role in controlling reproductive function and its widespread use for the treatment of reproductive disorders (for review see: Karten and Rivier). Very recently, a novel family of hypothalamic neuropeptides has been discovered which may be involved in the link between reproductive function and nutrition. Due to their structural similarity with an appetite-related family of peptides, the hypocretins, the authors termed these novel peptides orexins, after the Greek word "orexis" meaning appetite (Sakurai, 1998). Three lines of evidence from studies in rats support this hypothesis: First, immunohistochemical studies have shown that the distribution of orexin fibres overlaps with the GnRH neuronal system in the septo-preoptic area and the arcuate nucleus-median eminence region (Peyron et al. 1998). Second, intracerebral infusion of orexin (-A and -B) rapidly stimulates LH secretion in a dose- and time-dependent fashion in estradiol-primed, progesterone-treated, ovariectomised females (Pu et al. 1998). By contrast, both orexins inhibited LH release in ovariectomised rats that had not been primed with steroids, suggesting an interaction between orexin and steroids in the control of GnRH secretion (Pu et al. 1998). Third, terminals containing orexin have been found in the vicinity of neurons containing NPY and receptors for leptin (Horvath et al, 1999). Leptin and NPY are also thought to be part of the link between nutrition and reproduction (Grinspoon et al, 1996). The purpose of this project is to study the molecular basis of GPCR signaling and trafficking pathways that are involved in both reproductive events and obesity. We will focus on two different members of the GPCR family that target gonadotropin-releasing signaling pathways; the ligand for one, gonadotropin-releasing hormone (GnRH), has been known for several decades whilst that for the other, the orexins, was only discovered in the past year.
This project is been conducted in collaboration with Dr Karen Eidine, The Western Australian Institute for Medical Research Inc.
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Clare Berry - BSc
Role of p73, a p53 related protein in ovarian cancer.
My project aims to look at the expression and quantification of p73 family members in varied ovarian models. Namely I will be looking at TAp73 (full-length p73), DNp73 and Ex2Del p73 (both truncated isomers of p73) in ovarian cancer cell lines OVCAR-3 and SKOV-3, and over the rat ovulation cycle. Treatment of the cell lines with cisplatin doses and quantification of any differences will also be measured against non-treated cells. After these initial experiments I would also like to explore the expression of the three genes in p73 over-expressed cells. It will be interesting to note the different levels of these genes in such conditions, as p73 also induces DNp73. Further to this, I would like to try to block the pathway between p73 and DNp73 to see whether cisplatin treatment in ovarian cancer cells causes them to apoptose more effectively than with the pathway uunblocked.
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Wnt signalling and Secreted Frizzled-Related Protein (sFRP4) in breast tumour
It is well recognized that deregulation of homeostatic mechanisms controlling cell proliferation and death plays a critical role in tumorigenesis. Activation of apoptotic death pathways is the primary mechanism by which both cytotoxic drugs and immune cells kill cancer cells. Defects in apoptotic signalling and regulation are thought to be significant contributors to resistance to anti-tumour therapy. Our laboratory has investigated several signalling molecules and among the molecules we have investigated are components of the Wnt signalling pathway and in particular sFRP4. The Wnt proteins activate a number of signalling pathways that play a key role in cell proliferation, differentiation, apoptosis and tissue morphogenesis. Aberrant activation of Wnt signalling pathways with consequences for cell survival and proliferation have been described in a variety of cancers. sFRP4 is a member of a family of secreted glycoproteins which may regulate signalling by Wnts. sFRPs are principally believed to antagonize Wnt signalling, and this is consistent with their frequent downregulation in carcinomas and postulated role as tumour suppressors. However recent evidence suggests that the role of sFRPs is somewhat more complex and depends upon context and cell type. The details of the mechanisms by which sFRP4 and the sFRPs in general regulate Wnt signalling remains to be elucidated. sFRP-4 is expressed in breast tumours, however it not expressed in normal breast tissue. I am therefore concerned with the role sFRP-4 is playing within breast tumours. Using a breast cell line (MCF-7) I am exploring the expression patterns of sFRP-4 and the wnt signaling counterparts in normal growth medium and with various treatments. I am also investigating the expression pattern of sFRP-4 in human breast tumours using a tissue micro arrays system and correlating the expression patterns with patient data such as tumour grade and survival rate to explore the significance of sFRP-4 expression.
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Simon Mahoney - BSc
Role of Inhibitor of Apoptosis Protein (IAP) in ovarian cancer.
My study looked at ovarian cancer and its ability to acquire resistance to chemotherapy treatment. The focus was on X-Linked Inhibitor of Apoptosis Protein (XIAP), a protein from the Inhibitor of Apoptosis (IAP) family. IAPs were first discovered in baculoviruses, where they are used to prevent the host cell from entering into apoptosis and increasing the viral ability to reproduce. XIAP is one of seven current mammalian homologues of the baculovirus IAPs and is one of the most ubiquitously expressed IAP members. The expression of XIAP in a cell prevents apoptosis from occurring by binding to and preventing activation of multiple extrinsic and intrinsic cell death pathways. Apoptosis or programmed cell death is a physiological cell death program that is highly conserved among all animals. This regulated process of cell death plays a critical role during embryogenesis, tissue homeostasis and remodeling, and serves to remove unwanted cells such as self-reactive lymphocytes, tumor cells, cells with irreparable DNA damage or those infected with viruses. Insufficient apoptosis thus contributes to the pathogenesis of cancer, autoimmune disorders and sustained viral infection, while excessive apoptosis results in inappropriate cell loss and consequently degenerative disorders. In ovarian cancer we see a high expression of XIAP and a concurrent low level of apoptosis. By comparing two ovarian cell lines, one chemosensitive (OVCAR-3) and one chemoresistant (SKOV-3), we wanted to show whether differences between expression and stabilisation of XIAP can reflect in the cells ability to resist current chemotherapy treatments. Ovarian cancer can be characterised as either highly resistant to chemotherapy treatment, or after initially successful treatment the tumour cells can become highly refractory and resistant to treatment; the ability to gain resistance is what my projects main aim focussed on. We found that protein expression levels of XIAP do not differ between chemoresistant and chemosensitive cell lines, but that chemotherapy treatment will result in degradation of XIAP in the chemosensitive cell line to below detectable levels, while the chemoresistant cell line showed a statistically significant decrease in XIAP expression, with a slight corresponding increase in apoptosis. Analysis of XIAP and Caspase-3 mRNA expression levels by real-time PCR analysis indicated that chemotherapy induced knockdown of XIAP mRNA expression was similar between both the cell lines. Caspase-3 is the major effector pathway in apoptosis, and activation results in fragmentation of the DNA into 185base pairs, measuring caspase-3 levels is a method of analysing potential apoptotic changes in cells. We found that caspase-3 increased significantly in the chemoresistant cell line only, with only a slight corresponding increase in apoptosis. Analysis of the results indicated that XIAP is a major factor in chemoresistance occurring in ovarian cancer, and that stabilisation of XIAP by pathways, like Akt, can be a co-factor in this resistance to treatment.
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Localisation of caspsae-14 in the placenta and its implication in apoptosis.
The aim of my project is to elucidate the role of apoptosis in the placenta during normal development and pre-eclampsia. The placenta is a complex organ providing the ambient environment for the fetus, and has important functions controlling fetal and maternal metabolism. During development and in disease, the placenta undergoes remodelling of the villous structure in reaction to the changing balance of fetal demands and maternal supply. The placenta plays a crucial role in human development, and placental disease is a major factor in stillbirths, fetal growth restriction, neonatal disease, cardiovascular disease in adults, and cerebral palsy. Remodelling is a coordinated balance of cell proliferation and cell death by apoptosis, and the latter has a crucial role in placental development and disease. I have been specifically looking at caspase-14, a novel caspase in the overall regulation of placental apoptosis/proliferation and differentiation.
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