Role For Zinc And ZIP2 In The Action Of Nitric Oxide And In Vascular Protection Against Cigarette Smoke And Cardiovascular Disease
Funder
National Health and Medical Research Council
Funding Amount
$685,941.00
Summary
The NO/cGMP signalling pathway, which is central to cardiovascular physiology and protection against disease, is only fully effective when there are adequate levels of zinc in the vascular endothelium. This is especially important where zinc stores are depleted (elderly, smokers, diabetics and kidney disease). There is an urgent clinical need to implement strategies to monitor vascular Zn status. This application will explore the underlying science and translate these to the clinic.
Alveolar Macrophage Zinc And Zinc Transporters And Their Role In Phagocytosis
Funder
National Health and Medical Research Council
Funding Amount
$288,975.00
Summary
Zinc is an essential dietary component that serves a number of functions in the lungs. It is both an anti-oxidant and anti-inflammatory agent. Some airway inflammatory diseases such as emphysema may involve a critical loss of lung zinc. We believe that cigarette smoke causes the loss of zinc and this prevents the lung macrophages from working properly to clear bacteria and dead cells. This will provide a foundation for our long term goals of better clinical management of emphysema.
Airway Epithelial IAPs And Their Interaction With Zn Ions
Funder
National Health and Medical Research Council
Funding Amount
$260,779.00
Summary
The air we breathe contains a variety of harmful substances. Damage to the lining involves death of the ciliated cells that line the airways. We have shown that zinc protects these cells from premature death. This application focuses on a family of proteins called IAPs which bind zinc and regulate cell death in other tissues. This project focusses on how the IAPs and Zn may act together to mainitain healthy airways and how abnormalities of these may occur in people with asthma.
Role Of Zinc In The Respiratory Epithelium And Asthma
Funder
National Health and Medical Research Council
Funding Amount
$224,250.00
Summary
This project will use a panel of Zinquin-derived Zn fluorophores developed in our laboratory, as well as probes for the mammalian family of vesicular ZnT transporters, to carry out a study of the normal physiology of Zn in the respiratory system and potential abnormalities of this in patients with chronic inflammatory respiratory disease (asthma, COPD, chronic smoking). Chronic inflammatory diseases of the respiratory tract affect a significant proportion of the Australian community. For example ....This project will use a panel of Zinquin-derived Zn fluorophores developed in our laboratory, as well as probes for the mammalian family of vesicular ZnT transporters, to carry out a study of the normal physiology of Zn in the respiratory system and potential abnormalities of this in patients with chronic inflammatory respiratory disease (asthma, COPD, chronic smoking). Chronic inflammatory diseases of the respiratory tract affect a significant proportion of the Australian community. For example, asthma affects 12% of adults and amongst these, 15% waken weekly or more often with their asthma while 6% are hospitalized annually. There is a need to understand the basic mechanisms underlying these diseases so that new strategies can be developed to modify bronchocondtriction and inflammation. The project will provide new knowledge concerning the physiology of Zn in the respiratory epithelium and interactions between Zn deficiency and oxidants on injury in the respiratory tract. The usefulness of easily accessible nasal epithelial cells as a measure of Zn and Zn transporter levels deeper in the respiratory tract will be assessed. The project encompasses a number of fields and utilizes in vitro cellular and animal models, as well as tissues from human subjects.Read moreRead less
Trafficking Mechanisms Governing Receptor Availability For Signalling
Funder
National Health and Medical Research Council
Funding Amount
$526,978.00
Summary
Receptors on the cell surface allow cells to respond to their environment. We have recently discovered a new pathway for controlling the amount of receptors displayed on the cell surface, errors within which will lead to defects in development and diseases like cancer. We are studying how this new pathway controls the balance between how much receptors are destroyed after being activated and how much are recycled back for re-use.
A study of the nongenomic action of Vitamin D: proposed role of the nuclear VDR and downstream signalling molecules. Vitamin D (1,25D) activates genes in the nucleus through the vitamin D receptor (VDR). 1,25D can also elicit rapid responses at the plasma membrane. This action is critical to the activation of nuclear genes. We hypothesise that a proportion of the nuclear VDR is located at the plasma membrane where it stimulates downstream signalling molecules eg Ras, ERK1/2 and ERK5. We plan to ....A study of the nongenomic action of Vitamin D: proposed role of the nuclear VDR and downstream signalling molecules. Vitamin D (1,25D) activates genes in the nucleus through the vitamin D receptor (VDR). 1,25D can also elicit rapid responses at the plasma membrane. This action is critical to the activation of nuclear genes. We hypothesise that a proportion of the nuclear VDR is located at the plasma membrane where it stimulates downstream signalling molecules eg Ras, ERK1/2 and ERK5. We plan to explore this hypothesis and to identify the signalling molecules. We will also investigate our novel finding that a specific Ras isoform is involved in ERK5 activation. The work will provide new information on signalling pathways.Read moreRead less
Preclinical Evaluation Of The Novel Therapeutic Compound APP96-110 In An Ovine Model Of Traumatic Brain Injury
Funder
National Health and Medical Research Council
Funding Amount
$874,734.00
Summary
Traumatic brain injury (TBI) is a significant cause of death and disability, and yet there are currently no effective treatments to improve outcome following such an insult. Our laboratory has developed a novel therapeutic compound, by identifying an endogenous neuroprotective molecule, in the amyloid precursor protein and then identifying the active site and modifying it to improve its efficacy. We will be testing this compound in our sheep model of TBI.
Is Abdominal Discomfort A “colonic Itch”? Identification Of Itch Specific Pathways In The Gut In Health And Disease.
Funder
National Health and Medical Research Council
Funding Amount
$906,996.00
Summary
Chronic abdominal pain is a major worldwide problem. TGR5 and Mrgpr receptors are expressed by neuronal pathways innervating the skin, where they detect irritants and transmit itch. Our novel, innovative project shows a similar pathway exists within the viscera, which plays a major and unappreciated role in chronic abdominal pain. These receptors represent novel targets for therapeutic treatment, potentially creating multibillion-dollar savings to the Australian economy and healthcare systems.
GABA(B) Receptor Modulation Of Gastrointestinal Function In Health And Disease By Alpha-Conotoxins
Funder
National Health and Medical Research Council
Funding Amount
$689,050.00
Summary
Chronic visceral pain is a common and debilitating condition arising from numerous diseases that affect our internal organs. There is a desperate need for more information about the mechanisms responsible for signalling chronic visceral pain to provide therapies and potentially find a cure for it. Our research focuses on ?-conotoxins (small peptides from marine cone snail venom) as novel potential therapeutic agents for the treatment of chronic visceral pain.
Identifying The Underlying Causes Of Chronic Visceral Pain And Discovering Novel Therapeutic Treatments
Funder
National Health and Medical Research Council
Funding Amount
$470,144.00
Summary
Chronic pain is a major, but under appreciated social, clinical and economic challenge. Globally >1.5 billion people suffer from chronic pain. In the USA alone pain is the leading cause of disability, affecting 115 million adults and costing >$630 billion, more than cancer, heart disease and diabetes combined. By using pre-clinical models and translational science this proposal will identify the key mechanisms underlying chronic pain and also identify novel targets for new therapeutic trea ....Chronic pain is a major, but under appreciated social, clinical and economic challenge. Globally >1.5 billion people suffer from chronic pain. In the USA alone pain is the leading cause of disability, affecting 115 million adults and costing >$630 billion, more than cancer, heart disease and diabetes combined. By using pre-clinical models and translational science this proposal will identify the key mechanisms underlying chronic pain and also identify novel targets for new therapeutic treatmentRead moreRead less