Identification And Characterization Of Novel Bioactive Peptides From Australian Conesnails Targeting Pain Pathways
Funder
National Health and Medical Research Council
Funding Amount
$320,803.00
Summary
In recent years, significant advances have been made in the identification of new targets in the central or peripheral nervous systems which may be used to develop new pain killers. However, molecules specifically targeting these receptors and channels are lacking to date. This project will use novel cell-based approaches to find new molecules from conesnails which specifically target receptors involved in pain. These will be useful to increase our understanding of the mechanisms of pain.
Modulation Of Asthmatic Airway Inflammation By Activation Of Epithelial Proteinase Activated Receptors
Funder
National Health and Medical Research Council
Funding Amount
$188,912.00
Summary
Children and adults feel the symptoms of asthma because their airways close up too easily. We have discovered a new mechanism that the healthy lung uses to keep airways open. The epithelial cells which line the airway release an enzyme that cuts of a small part of another protein, called a PAR receptor, that sits on the same cell. When this happens the epithelial cell releases relaxing substances from their lower surface. The relaxing substances keep the airways open. This grant application is d ....Children and adults feel the symptoms of asthma because their airways close up too easily. We have discovered a new mechanism that the healthy lung uses to keep airways open. The epithelial cells which line the airway release an enzyme that cuts of a small part of another protein, called a PAR receptor, that sits on the same cell. When this happens the epithelial cell releases relaxing substances from their lower surface. The relaxing substances keep the airways open. This grant application is designed to test whether the relaxing system also stops the airways from developing inflammation. If the relaxing system does this we will be able to use the knowlege we have that lets us activate the PAR receptors artificially to design new types of drugs. These drugs would be better than existing asthma drugs because they would prevent inflammation and relax the airways at the same time. These drugs could also be useful in other lung diseases such as chronic bronchitis.Read moreRead less
Impact Of Airway Wall Fibrosis On The Efficacy Of Anti-asthma Drugs
Funder
National Health and Medical Research Council
Funding Amount
$432,750.00
Summary
Most episodes of asthma are controlled or prevented by current medications. In a small, but significant proportion of asthmatics (5-10%) symptoms persist despite the use of the best combinations of anti-asthma drugs. One of the reasons that acute episodes of asthma occur is that the airway tubes slowly change in structure. These changes involve an increase in the amount of collagen (part of the cement between cells) making the airway stiffer. In this project, we are exploring the impact of the s ....Most episodes of asthma are controlled or prevented by current medications. In a small, but significant proportion of asthmatics (5-10%) symptoms persist despite the use of the best combinations of anti-asthma drugs. One of the reasons that acute episodes of asthma occur is that the airway tubes slowly change in structure. These changes involve an increase in the amount of collagen (part of the cement between cells) making the airway stiffer. In this project, we are exploring the impact of the stiffening of the airway on the way that different cells within the airway wall respond to drugs used to treat asthma. Our initial findings suggest that when the airway wall becomes stiffer with more collagen, there is a diminished benefit from the anti-asthma drugs. This new study is designed to identify the molecular mechanisms for the poor response to the anti-asthma drugs. With this knowledge it will be easier to design and test new drugs that are more effective in severe asthma.Read moreRead less
Hormonal Modulation Of Prostatic Growth And Contractility
Funder
National Health and Medical Research Council
Funding Amount
$324,237.00
Summary
With increasing age human males are likely to develop benign prostatic hyperplasia (BPH), a disorder characterized by urethral obstruction due to an increase in size of the prostate gland. Drug treatments of this condition are not entirely satisfactory and the current project is to examine the mechanisms by which the prostate grows and occludes the urethra. We will use human prostate cells grown in artificial conditions to determine which hormones alter the types of cells and especially examine ....With increasing age human males are likely to develop benign prostatic hyperplasia (BPH), a disorder characterized by urethral obstruction due to an increase in size of the prostate gland. Drug treatments of this condition are not entirely satisfactory and the current project is to examine the mechanisms by which the prostate grows and occludes the urethra. We will use human prostate cells grown in artificial conditions to determine which hormones alter the types of cells and especially examine those cells which can contract as these may be of critical importance in the urethral obstruction. We hypothesize that an enzyme called protein kinase C may be implicitly involved in both cell growth and contractile function and we will examine the role of protein kinase C with a view ultimately to develop drugs which may interfere with this process and therefore aid in non-surgical treatment of the condition.Read moreRead less
The Pharmacology And Physiology Of GABA-C Receptors
Funder
National Health and Medical Research Council
Funding Amount
$481,980.00
Summary
GABA is one of the most important chemicals in the brain. GABA and its associated receptors (GABA receptors) work together to keep the balance between neuronal excitation and inhibition which is required for normal brain function. There are three types of GABA receptors called GABA-A, GABA-B and GABA-C receptors. Chemicals acting at these receptors may be therapeutically useful in treating neurological probles such as epilepsy, anxiety, depression and memory-related disorders associated with Alz ....GABA is one of the most important chemicals in the brain. GABA and its associated receptors (GABA receptors) work together to keep the balance between neuronal excitation and inhibition which is required for normal brain function. There are three types of GABA receptors called GABA-A, GABA-B and GABA-C receptors. Chemicals acting at these receptors may be therapeutically useful in treating neurological probles such as epilepsy, anxiety, depression and memory-related disorders associated with Alzheimer's disease and schizophrenia. GABA-A and GABA-C receptors are members of the ligand-gated ion channel super family in which the ion channel forms an intergral and central part of the receptor. In response to GABA, the channel opens and chloride ions flow through the channel. This causes an inhibitory action i.e. the cell reduces its rate of firing. This project aims to study GABA-C receptors by investigating what proteins make up the ion channel, by studying the actions of a range of chemicals that have specific effects at these receptors and by identifying amino acids that are important for normal channel function. New chemicals identified in our studies will provide leads for the design and development of new therapeutic agents acting on the brain.Read moreRead less
Targeting Post-translational Modifications In TRPV Pain Channels
Funder
National Health and Medical Research Council
Funding Amount
$480,127.00
Summary
The same nerve receptor that binds the pungent component of chilli peppers (TRPV1) is an important part of our pain pathway. TRPV1 also responds to painful heat and acids. Chronic pain is an important unmet medical need and it uses the TRPV1 pathway. After activation by chilli, a feedback system in nerves inactivates TRPV1 and stops pain signalling. This feedback changes in chronic pain. This project aims to understand and exploit this feedback mechanism to find new approaches to pain therapy.
Pharmacological Regulation Of Airway Smooth Muscle Phenotype
Funder
National Health and Medical Research Council
Funding Amount
$276,742.00
Summary
In Australia there is a high incidence of asthma which impairs quality of life and can sometimes cause death if sufficiently severe. The main cause of asthma is the shortening of muscle surrounding the airway passages that cause the narrowing of these tube-like passages. When airway passages narrow a feeling of chest tightness is perceived by the asthmatic patient. When the narrowing is severe the amount of oxygen being delivered to the blood can be reduced to dangerous levels. When there is mus ....In Australia there is a high incidence of asthma which impairs quality of life and can sometimes cause death if sufficiently severe. The main cause of asthma is the shortening of muscle surrounding the airway passages that cause the narrowing of these tube-like passages. When airway passages narrow a feeling of chest tightness is perceived by the asthmatic patient. When the narrowing is severe the amount of oxygen being delivered to the blood can be reduced to dangerous levels. When there is muscle growth in the airways even small amounts of shortening of the muscle can cause severe narrowing of the airway passages. This research will investigate how muscle grows in asthmatic airways and look for new ways to use drugs to treat this muscle growth. We hope to improve drug treatment of asthma by limiting the amount of airway narrowing caused by muscle contraction.Read moreRead less
Cellular Actions Of Cannabinoids Within The Spinal Cord Dorsal Horn In A Neuropathic Pain State
Funder
National Health and Medical Research Council
Funding Amount
$432,750.00
Summary
Morphine and other opioids are among the most important drugs used to treat moderate to severe pain. However, some clinically important chronic pain states are relatively insensitive to opioid treatment, such as neuropathic pain which is caused by injury to the nervous system. Human and animal studies indicate that the active ingredient of the plant cannabis sativa, THC, and a number of synthetic cannabis-like drugs (cannabinoids) also have analgesic, or pain relieving properties. Animal studies ....Morphine and other opioids are among the most important drugs used to treat moderate to severe pain. However, some clinically important chronic pain states are relatively insensitive to opioid treatment, such as neuropathic pain which is caused by injury to the nervous system. Human and animal studies indicate that the active ingredient of the plant cannabis sativa, THC, and a number of synthetic cannabis-like drugs (cannabinoids) also have analgesic, or pain relieving properties. Animal studies have shown that cannabinoids potentiate the analgesic effects of opioids. Of particular interest is the finding that cannabinoids reduce the abnormal pain symptoms associated with animal models of neuropathic pain, such as that caused by nerve injury. Several brain regions play a pivotal role in the analgesic actions of both opioids and cannabinoids. In previous studies I have identified the cellular mechanisms by which opioids and cannabinoids produce their analgesic effects in single cells within the brain. In addition, the spinal cord is the initial relay point of painful stimuli entering the central nervous system and is a major site of opioids and cannabinoid analgesic actions. However, the cellular mechanisms underlying cannabinoid and opioid actions within the spinal cord, particularly in pathways which transmit ascending pain information to the brain, are less well understood. In addition, the cellular actions of cannabinoids and opioids in neuropathic pain states are unknown. The proposed study will determine the cellular mechanisms underlying the analgesic actions of cannabinoids and opioids in single neurons identified as belonging to pain pathways within the spinal cord in normal and nerve injured animals. These techniques have the potential to identify analgesic combinations between cannabinoids, opioids and other agents with enhanced therapeutic activity and reduced side effects.Read moreRead less