Molecular Characterization Of E-cadherin-activated Rac Signaling
Funder
National Health and Medical Research Council
Funding Amount
$220,500.00
Summary
Interactions between cells and their neighbouring cells control many important processes in the body. The adhesion molecule, E-cadherin, is a major protein that controls interactions between cells in epithelial tissues (e.g. breast, lung, gut). E-cadherin is essential for these tissues to form normally, and loss of E-cadherin function contributes to the progression of many human cancers (especially common cancers such as breast and lung). Understanding how E-cadherin controls normal epithelial c ....Interactions between cells and their neighbouring cells control many important processes in the body. The adhesion molecule, E-cadherin, is a major protein that controls interactions between cells in epithelial tissues (e.g. breast, lung, gut). E-cadherin is essential for these tissues to form normally, and loss of E-cadherin function contributes to the progression of many human cancers (especially common cancers such as breast and lung). Understanding how E-cadherin controls normal epithelial cell function will therefore provide key insights into the bases for tumor progression. In this study we will examine how E-cadherin signals to the interior of cells. We have recently discovered a new signaling pathway that is turned on when E-cadherin is activated. Understanding the fundamental elements of this signaling pathway will provide invaluable insights into how cells recognize one another during health and disease.Read moreRead less
Characterization Of The Phosphoinositide 5-phosphatase SKIP.
Funder
National Health and Medical Research Council
Funding Amount
$505,523.00
Summary
Growth factors and insulin stimulate a complex array of signals inside the cell, which are important for both cell survival and metabolism. A central intracellular signaling enzyme that initiates lipid messages that promote glucose uptake into the cell and promote cell survival is that generated by the PI3-kinase. This enzyme has increased activity in many cancers, and is also important in diabetes when the enzyme may be suppressed. Our grant proposes to investigate the function of another enzym ....Growth factors and insulin stimulate a complex array of signals inside the cell, which are important for both cell survival and metabolism. A central intracellular signaling enzyme that initiates lipid messages that promote glucose uptake into the cell and promote cell survival is that generated by the PI3-kinase. This enzyme has increased activity in many cancers, and is also important in diabetes when the enzyme may be suppressed. Our grant proposes to investigate the function of another enzyme called SKIP which acts within the cell to oppose the functions of the PI3-kinase. Several lines of evidence indicate SKIP may be important in both development and cancer. SKIP has been identified as a putative candidate gene for a developmental disorder known as Miller Dieker syndrome. This disease is associated with facial and significant brain abnormalities. In addition the SKIP gene is located on a chromosome that is frequently deleted in breast and colon cancer. SKIP is an enzyme that functions to remove phosphate molecules from PI3-kinase signaling molecules. SKIP has been shown to prevent glucose uptake into the cell by breaking down PI3-kinase signals. We have recently demonstrated SKIP phosphatase activity can be inhibited by binding to another protein called suppressor of death domains (SODD). We plan to investigate the effects this complex has on SKIP enzyme activity, and how this complex plays a role in regulating PI3-kinase signals that promote glucose uptake. Secondly, we plan to investigate the function of SKIP in an intact animal by making mice which lack SKIP(knock out mice). Given SKIP is implicated in a developmental syndrome and insulin signaling, we can delineate the functional significance of SKIP and the molecular pathways regulated by this enzyme.Read moreRead less
Role Of The Inositol Polyphosphate 4-phosphatase Type 2 In Human Breast Cancer
Funder
National Health and Medical Research Council
Funding Amount
$611,032.00
Summary
Breast cancer is the most invasive cancer in females, affecting 1 in 9 women before the age of 85. Normally cells only divide when they receive a stimulus from a hormone or growth factor. The PI3K pathway responds to these stimuli and has been implicated in cancer when cells divide uncontrollably and invade surrounding tissue. We have identified a potential cancer suppressing gene, 4-ptase-2 that turns off the PI3K growth signals. We aim to characterize the role of 4-ptase-2 in breast cancer.
In the asthmatic lung structural changes, such as increased deposition of proteins which form the scaffolding of the airways (the extracellular matrix proteins), and an increased mass of bronchial smooth muscle cells occur. Many of these critical structural changes are not reversed or prevented with current asthma therapy, thus we need to investigate, by using lung cells and tissues , why they happen and how we can prevent them.
AMP-activated Protein Kinase (AMPK) In Acute Renal Failure
Funder
National Health and Medical Research Council
Funding Amount
$401,523.00
Summary
Acute renal failure is a common complication of any severe illness. Generally, it is the lack of blood flow, or food that leads to this problem. People who are ill are unable to provide adequate blood flow to their kidneys, so the kidneys become diseased and fail to function. This can be fatal. There are, however, mechanisms in the kidney that are designed to avoid this shortage of energy. The aim of these studies is to find out what these protective mechanisms usually do in the kidney, and unde ....Acute renal failure is a common complication of any severe illness. Generally, it is the lack of blood flow, or food that leads to this problem. People who are ill are unable to provide adequate blood flow to their kidneys, so the kidneys become diseased and fail to function. This can be fatal. There are, however, mechanisms in the kidney that are designed to avoid this shortage of energy. The aim of these studies is to find out what these protective mechanisms usually do in the kidney, and understand why they are not more active. We hope to find ways to switch them on earleir, using drugs, so as to protect the kidneys from injury.Read moreRead less
C-Jun N-terminal Kinase Regulation Of Microtubule Destabilizer, Stathmin - A Novel Cytoprotective Pathway
Funder
National Health and Medical Research Council
Funding Amount
$550,230.00
Summary
The loss of heart muscle cells during heart attack and heart failure worsens the severity of heart disease. We will study how to protect heart muscle cells by identifying the molecules involved in controlling survival responses. We will use this knowledge to prevent heart muscle cells from dying when exposed to a range of normally harmful conditions. Our study has the potential to prevent heart muscle cell loss, improve heart function and prevent muscle damage in heart disease.
Physiological Effects Of Manipulating AMP-activated Kinase Genes
Funder
National Health and Medical Research Council
Funding Amount
$351,110.00
Summary
The AMP-activated protein kinase is a metabolic stress sensing protein kinase responsible for matching the supply of energy to the body's functions. During vigorous exercise it senses metabolic stress (reduction in energy) caused by muscle contraction and stimulates glucose uptake and burning of fat to provide energy. The AMP-activated protein kinase also regulates the production of nitric oxide that is important in controlling blood pressure and blood clotting. Reduced caloric intake activates ....The AMP-activated protein kinase is a metabolic stress sensing protein kinase responsible for matching the supply of energy to the body's functions. During vigorous exercise it senses metabolic stress (reduction in energy) caused by muscle contraction and stimulates glucose uptake and burning of fat to provide energy. The AMP-activated protein kinase also regulates the production of nitric oxide that is important in controlling blood pressure and blood clotting. Reduced caloric intake activates the AMP-activated protein kinase to suppress energy consuming activities and modify the expression of genes. Many of the conditions that activate the AMP-activated protein kinase (exercise, reduced caloric intake) are associated with a healthy life style, increased longevity and resistance to age onset diseases including cardiovascular disease (atherosclerosis, hypertension), obesity, neurodegeneration and diabetes. By manipulating the gene for the AMP-activated protein kinase in mice we expect to learn more about its key physiological roles and give new insight into the control of age onset diseases.Read moreRead less