Cyclin Dependent Kinases As Drug-Targets To Reduce Renal Cyst Formation And Scarring In Polycystic Kidney Disease
Funder
National Health and Medical Research Council
Funding Amount
$319,446.00
Summary
Polcystic kidney disease (PKD) is one of the most common genetic diseases in humans. The most common type (autosomal dominant-PKD) affects approximately 1:400 to 1:1000 individuals worldwide. Kidney failure is the most debilitating and serious complication of PKD, and it accounts for approximately 10% of the cases of end-stage kidney requiring artificial kidney treatment (dialysis) or transplantation. Over the last decade, major advances have been made in preventing kidney failure due to diabeti ....Polcystic kidney disease (PKD) is one of the most common genetic diseases in humans. The most common type (autosomal dominant-PKD) affects approximately 1:400 to 1:1000 individuals worldwide. Kidney failure is the most debilitating and serious complication of PKD, and it accounts for approximately 10% of the cases of end-stage kidney requiring artificial kidney treatment (dialysis) or transplantation. Over the last decade, major advances have been made in preventing kidney failure due to diabetic kidney disease, but these are ineffective for PKD. As such, currently, there is no treatment to prevent kidney failure due to PKD, and new therapies are needed. PKD is characterised by the development of multiple cysts in the kidney, which enlarge and destroy normal kidney tissue. The growth of the cysts is due to uncontrolled growth (cell division) of the cells of the kidney (epithelial cells), which causes cyst formation. In recent years, gene mutations in proteins called polcysytins are thought to be responsible for the cause of the disease. However, the genetic mutations in PKD are complex (>30 types for autosomal dominant PKD alone), and it is unlikely that gene therapy will be possible with current technology in the near future. A simpler approach is to develop 'drugs' that target the consequences of the mutation. This project will investigate the role of a group proteins, called cyclin-dependent kinases (CDKs) in PKD. CDKs which are enzymes that are critical in promoting cell division. Our preliminary data shows that CDKs are upregulated in PKD. The aim of this project is to establish the importance of CDKs in PKD, and examine the effect of new drugs (CDK inhibitors) in maintaining in preventing cyst growth and kidney scarring in PKD. CDK inhibitors are currently being tested in phase 1 and 2 clinical trials in patients with cancer, and this will facilitate the translation of the findings of this project to humans with PKD.Read moreRead less
The Mechanism By Which Apical-basal Polarity Complexes Regulate The Salvador-Warts-Hippo Pathway
Funder
National Health and Medical Research Council
Funding Amount
$540,099.00
Summary
Cancer is a multi-hit process involving the activation of critical signaling pathways leading to increased proliferation, survival and increased invasion-metastasis. We have discovered that a neoplastic tumour suppressor gene, lgl, acts though the Salvador-Warts-Hippo (SWH) tumour suppressor pathway to inhibit cell proliferation and cell survival. Here we use the model organism, Drosophila, and mammalian epithelial cells to determine the mechanism by which Lgl activates the SWH pathway.
The Tumour Suppressor Lgl In The Regulation Of Cell Signaling, Proliferation And Apoptosis
Funder
National Health and Medical Research Council
Funding Amount
$534,871.00
Summary
Cancer is a disease that affects 1-3 people at some point in their lifetime. Therefore, understanding what causes cancer is of major importance to medical science. This proposal focuses on a group of tumour suppressors, Scrib-Dlg-Lgl, which act in a common pathway to regulate cell polarity (cell shape) and proliferation. We have shown that Lgl also regulates cell death. This proposal focuses on understanding the mechanism by which Lgl regulates the cell proliferation and death machinery.
Understanding SOCS3 Inhibition Of JAK Activity In Myeloproliferative Disorders
Funder
National Health and Medical Research Council
Funding Amount
$524,820.00
Summary
The myeloproliferative disorders are diseases in which abnormal blood cell development leads to a risk of stroke, thrombosis, hemorrhage and leukemia. Remarkably, three of these disorders are caused by an error in a single enzyme that makes it over active. The enzyme, JAK2, controls how cells respond to hormone-like messengers called cytokines. We are investigating a cellular pathway that inhibits this enzyme in order to understand the progression and potential treatment of the disorders.
Adult Stem Cell Transplantation Therapy In Parkinsonian Rat
Funder
National Health and Medical Research Council
Funding Amount
$526,517.00
Summary
Parkinson's disease is a progressive neurodegenerative disorder characterised by slowness of movement, muscle rigidity and tremor. It affects about 1% of the population at age 50 and 10% over age 80. Symptoms are caused by low levels of dopamine, a chemical in the brain that helps control movement. The symptoms increase in severity with time, leading to increasing difficulty in walking, speaking, writing, swallowing and sleeping and increasing the incidence of broken bones from falls. Parkinson' ....Parkinson's disease is a progressive neurodegenerative disorder characterised by slowness of movement, muscle rigidity and tremor. It affects about 1% of the population at age 50 and 10% over age 80. Symptoms are caused by low levels of dopamine, a chemical in the brain that helps control movement. The symptoms increase in severity with time, leading to increasing difficulty in walking, speaking, writing, swallowing and sleeping and increasing the incidence of broken bones from falls. Parkinson's disease is incurable but the symptoms can be controlled with medications that replace the lost dopamine. Medications become less effective as the disease progresses and there is need for new therapies. Worldwide the hunt is on to discover new cell transplantation therapies to replace the dopamine in the brain and to prevent degeneration of the still surviving dopamine cells. Although embryonic stem cells might be useful for such therapies, they raise the risk of tumour formation from the transplanted cells. This aim of this proposal is to test, in parkinsonian rat, a therapy in which adult stem cells from the patient are transplanted into their own brain to provide a new source of dopamine. We have discovered a new and unique source of adult stem cells, the sense organ of smell in the nose. Small samples can be taken through the nose and we can grow these adult stem cells from people of all ages, including people with Parkinson's disease. As adult stem cells they avoid the ethical issues associated with embryonic stem cell transplantation and as cells from the same patient, they are not rejected by the immune system. This is being tested in principle by a world-first clinical trial in which we are taking another cell type from the nose, growing it in the lab, and transplanting into the injured spinal cord in a search for a cure for paraplegia. This project takes the first steps to developing a new treatment for Parkinson's disease using a patient's own adult stem cells.Read moreRead less
Kidney Mesenchymal Stem Cells In Tubular Development, Repair And Turnover
Funder
National Health and Medical Research Council
Funding Amount
$989,141.00
Summary
In Australia, 11.3% of deaths are associated with chronic kidney disease with >$1 billion per annum spent on treating this condition. At present, only dialysis and transplantation are available to treat end stage kidney disease. We have found a kidney stem cell population in both human and mouse that can form new epithelial structures. In this project, we will investigate the normal role played by these kidney stem cells and examine whether they can contribute to kidney regeneration.
Kidney Mesenchymal Stem Cells In Tubular Development, Repair And Turnover.
Funder
National Health and Medical Research Council
Summary
In Australia, 11.3% of deaths are associated with chronic kidney disease with >$1 billion per annum spent on treating this condition. At present, only dialysis and transplantation are available to treat end stage kidney disease. We have found a kidney stem cell population in both human and mouse that can form new epithelial structures. In this project, we will investigate the normal role played by these kidney stem cells and examine whether they can contribute to kidney regeneration.
Defining The Role Of Kidney CD103+Dendritic Cells For Treatment Of Chronic Kidney Disease
Funder
National Health and Medical Research Council
Funding Amount
$599,431.00
Summary
Chronic kidney disease (CKD) is a major cause of death and morbidity. Current treatments for CKD are not effective and new therapeutic approaches are needed. Dendritic cells (DCs) are key immune cells and play a central role in kidney disease. We recently found that a major DC subset called CD103+ DCs harmed the kidney in an animal model of human CKD. This study is to determine how CD103+ DCs cause kidney damage, and how to target CD103+ DCs for development of new therapies for human CKD.