Determining The Cellular Mechanisms Involved In The Airway Response To Topical Citrate
Funder
National Health and Medical Research Council
Funding Amount
$444,491.00
Summary
The air passages of the lungs are lined by mucous membranes. These membranes are covered by a thin layer of fluid to protect the airways from drying. This fluid allows the cilia, the hair like projections on top of the airway cells to beat more effectively to remove mucous and inhaled particles from the lungs. The volume and composition of this fluid is determined by the salt and water movement across the mucous membranes of the airways. These processes are abnormal in cystic fibrosis (CF), the ....The air passages of the lungs are lined by mucous membranes. These membranes are covered by a thin layer of fluid to protect the airways from drying. This fluid allows the cilia, the hair like projections on top of the airway cells to beat more effectively to remove mucous and inhaled particles from the lungs. The volume and composition of this fluid is determined by the salt and water movement across the mucous membranes of the airways. These processes are abnormal in cystic fibrosis (CF), the most common lethal inherited disease affecting Australians. In CF, an abnormal gene disrupts one of the major mechanisms for salt and water movement in the air passages. This abnormal salt transport causes drying of the airway surface which impairs the working of the cilia. This leads to retention of mucous in the airways with repeated bacterial infections damaging the lungs. Over the last 10 years, we have developed a series of simple tests to measure the abnormalities in the CF airway of human subjects. We have isolated an exciting new clinical application for sodium citrate, a substance used in blood transfusions. Citrate appears to alter both the salt transport abnormalities found in CF. This research proposal seeks to better understand the dual effects of citrate and to test similar compounds that may have stronger effects. The ultimate aim of our research is to have sufficient knowledge to work out the best way to develop a new treatment for CF.Read moreRead less
The Role Of Neuronal Hyper-excitability In An Animal Model Of Motor Neuron Disease
Funder
National Health and Medical Research Council
Funding Amount
$558,170.00
Summary
Every day at least one person in Australia dies of the fatal and untreatable adult neurodegenerative disease of amyotrophic lateral sclerosis (motor neuron disease). This research examines the factors driving early increases in neural activity which may lead to the loss of upper and lower motor neurons in adulthood. The use of new methods to suppress production of specific proteins causing increased neural activity may lead to novel treatments for this disease.
Engineering Subtype Selective Inhibitors Of Voltage-sensitive Sodium Channels
Funder
National Health and Medical Research Council
Funding Amount
$406,980.00
Summary
During efforts to find new inhibitors of voltage sensitive sodium channels (VSSCs), we have discovered two new families of mu-conotoxins from Australian Conus tulipa and C. striatus that inhibit neuronal and muscle forms of the tetrodotoxin-sensitive (TTX-S) sodium channel. From these and related analogues we have identified a number of selective and highly potent inhibitors of VSSCs, opening the possibility of producing the first subtype selective TTX-S inhibitors useful in diseases such as epi ....During efforts to find new inhibitors of voltage sensitive sodium channels (VSSCs), we have discovered two new families of mu-conotoxins from Australian Conus tulipa and C. striatus that inhibit neuronal and muscle forms of the tetrodotoxin-sensitive (TTX-S) sodium channel. From these and related analogues we have identified a number of selective and highly potent inhibitors of VSSCs, opening the possibility of producing the first subtype selective TTX-S inhibitors useful in diseases such as epilepsy and stroke. These analogues also showed high selectivity for TTX-S sodium channels over a TTX-resistant (TTX-R) subtype hPN3, a key channel involved in the transmission of neuropathic pain that we recently cloned from human dorsal root ganglia. Given that TTX-S and TTX-R sodium channels have the same overall structure but differ at a relatively small number of key positions likely to affect mu-conotoxin binding, we believe it is possible to reverse engineer mu-conotoxin pharmacology in favour of the TTX-R form. This project will engineer subtype specific inhibitors of sodium channels in nerves through an understanding of how and wheremu-conotoxin bind to the sodium channel. Our long-term goal is to produce sodium channel drug candidates using m-conotoxins as templates for the development of subtype selective inhibitors of TTX-S and TTX-R sodium channels. The results of this study are designed to maximise the potential of this class of peptides as leads to the development of a new classes of therapeutics for pain, epilepsy and stroke.Read moreRead less
Physiological Function Of Nedd4-2 In Regulating The Epithelial Sodium Channel
Funder
National Health and Medical Research Council
Funding Amount
$805,797.00
Summary
The epithelial sodium channel (ENaC) controls sodium balance, blood volume and blood pressure. Abnormal regulation of ENaC is associated with conditions such as hypertension and pulmonary oedema. Delineating the regulation of ENaC is vital in understanding disease mechanisms and in defining targets for novel therapeutics for the treatment of disorders that arise due to sodium imbalance. This grant will enable us to understand how ENaC is regulated by a novel protein known as Nedd4-2.