Inhibition Of Retinoblastoma Protein Degradation By Interaction With The Serpin PAI-2 Via A Novel Consensus Motif
Funder
National Health and Medical Research Council
Funding Amount
$463,500.00
Summary
Plasminogen activator inhibitor-2 (PAI-2) has previously been shown to inhibit the activity of enzymes outside the cell that are involved in blood clotting and cell migration. We have discovered that this activity is probably not the major role of PAI-2. PAI-2 also has a function inside cells that protect and increases the activity of an important tumour suppressor protein called the retinoblastoma tumour suppressor protein (Rb). Rb is involved in many cellular functions such as, cell death, cel ....Plasminogen activator inhibitor-2 (PAI-2) has previously been shown to inhibit the activity of enzymes outside the cell that are involved in blood clotting and cell migration. We have discovered that this activity is probably not the major role of PAI-2. PAI-2 also has a function inside cells that protect and increases the activity of an important tumour suppressor protein called the retinoblastoma tumour suppressor protein (Rb). Rb is involved in many cellular functions such as, cell death, cell differentiation, cell growth, and most importantly prevention of cancer development. Rb is attacked and destroyed by several viruses which causes cells to become cancerous. This grant seeks to fully understand how PAI-2 protects and interacts with Rb. We have already found a new site on Rb to which PAI-2 binds. This site is also used by other proteins in the cell as well as disease causing virus proteins. Examples of these proteins are BRCA1, a protein involved in breast cancer development, and EBNA6, a protein from Epstein Barr virus that causes glandular fever and tumours. We have also found, and seek to explore further, how PAI-2 reverses the activities of the cervical cancer causing proteins of the human papilloma virus. Although at an early stage, these studies may lead to the development of new therapeutic drugs based on PAI-2 for the treatment of various types cancers or warts caused by HPV. Analysing the activity of PAI-2 inside cells will have implications for understanding much of the confusing scientific literature on PAI-2 and will provide a better comprehension of the role of PAI-2 in inflammation, cell differentiation, wound healing and cancer. For example it has long been known that the presence of PAI-2 in cancerous tumours is linked with a better prognosis, an activity that can now be understood in terms of the PAI-2 interaction with Rb. This new understanding may lead to the development of PAI-2 based prognostic assays for cancer.Read moreRead less
Generation And Characterisation Of An Animal Model For Age-related Macular Degeneration
Funder
National Health and Medical Research Council
Funding Amount
$226,650.00
Summary
Age-Related Macular Degeneration (AMD) is the leading cause of irreversible blindness in the aged population in the developed world, and it is one of the least understood retinal diseases. AMD is a slow, progressive and painless condition that affects the macula, the small central part of the retina that allows one to see fine detail clearly. With the ever-increasing human life expectancy, the prevalence of AMD (15-30%) in the age group of over 75 years will significantly increase, causing enorm ....Age-Related Macular Degeneration (AMD) is the leading cause of irreversible blindness in the aged population in the developed world, and it is one of the least understood retinal diseases. AMD is a slow, progressive and painless condition that affects the macula, the small central part of the retina that allows one to see fine detail clearly. With the ever-increasing human life expectancy, the prevalence of AMD (15-30%) in the age group of over 75 years will significantly increase, causing enormous social and financial problems for the community. In spite of the significance of this problem, the exact cause of AMD is not yet known, and there is no permanent effective treatment or cure for the condition. One of the major obstacles hindering any advances towards the development of intervention strategies or therapies is the lack of an appropriate animal model. Currently, the animal models that are available for ocular diseases do not fit the human AMD situation. This project aims to characterize the first animal model for retinal degeneration caused by abnormal functioning of the retinal pigment epithelial cells (RPE). The main role of RPE cells is the phagocytosis and digestion of the continuously growing and shed light receptor segments in the eye. Their normal functioning therefore is vital to maintaining good vision. The availability of such an animal model will allow us to learn more about the changes that might occur in the eye leading to the development of AMD and to design strategies to prevent or delay progression of the condition.Read moreRead less
Epilepsy is an important human disease because it causes physical trauma and sudden death in addition to immense social and economic hardship. The genetic basis of a number of epilepsy syndromes has been identified but the precise mechanism whereby mutations produce seizures is unknown. Several mutations in the alpha4 neuronal nicotinic receptor (a4 nAChR) gene have been identified in Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (ADNFLE). This is a rare form of inherited epilepsy character ....Epilepsy is an important human disease because it causes physical trauma and sudden death in addition to immense social and economic hardship. The genetic basis of a number of epilepsy syndromes has been identified but the precise mechanism whereby mutations produce seizures is unknown. Several mutations in the alpha4 neuronal nicotinic receptor (a4 nAChR) gene have been identified in Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (ADNFLE). This is a rare form of inherited epilepsy characterized by the presence of seizures during light sleep. In vitro studies using the human mutated DNA (i.e. DNA containing the genetic defect) have suggested that this mutation results in reduced activity of the receptor. Therefore a mouse in which this gene is destroyed would be relevant in understanding the human disease. We have generated an a4 nAChR knockout (KO) mouse and plan to use the mouse to test the idea that loss of function of the a4 nAChR in vivo is associated with enhanced seizure activity. The KO mice do not have unprovoked seizures but appear to have an increased number of major motor seizures in response to pentylenetetrazole, an agent which is known to cause seizures by blocking the effects of the brain inhibitory molecule GABA. Interestingly, a4 nAChRs are known to control the release of GABA. We therefore propose that our knockout mice have seizures because they tend to under produce GABA. We will also make and analyse a mouse line with the same genetic mutation as patients with ADNFLE. The experiments are aimed at understanding the way that seizures are generated and spread in the brain in these rare forms of epilepsy. The hope is that understanding these mechanisms will help us better understand and therefore treat common forms of epilepsy.Read moreRead less
Progesterone Receptor-mediated Coordination Of Oocyte-oviduct Communication During Ovulation
Funder
National Health and Medical Research Council
Funding Amount
$86,128.00
Summary
Infertility affects 1 in 6 couples, often due to failed release of an egg from the ovary. The hormone progesterone is essential for this process. Our goal is to determine how progesterone signals the egg to ensure its correct release into the oviduct where fertilization may occur. To identify these signals, experiments will analyse ovary cells and eggs of mice, including mice that do not respond to progesterone. The results will provide much needed information about female reproductive health.