STRUCTURAL AND FUNCTIONAL INTERACTIONS BETWEEN THE II-III LOOP OF THE SKELETAL DHPR AND THE RYANODINE RECEPTOR
Funder
National Health and Medical Research Council
Funding Amount
$410,250.00
Summary
The project has implications for neuromuscular diseases and for muscle weakness in general and in the elderly, all of which are significant health issues. The results will elucidate molecular mechanisms in muscle contraction and will provide a basis for drug design and treatment of muscle disorders. Respiration and locomotion depend on changes in calcium concentration inside muscle cells. Cardiovascular function, neuronal activity and immune responses also depend on the release of calcium from i ....The project has implications for neuromuscular diseases and for muscle weakness in general and in the elderly, all of which are significant health issues. The results will elucidate molecular mechanisms in muscle contraction and will provide a basis for drug design and treatment of muscle disorders. Respiration and locomotion depend on changes in calcium concentration inside muscle cells. Cardiovascular function, neuronal activity and immune responses also depend on the release of calcium from internal stores. Ryanodine receptor (RyR) calcium channels, either alone or in combination with a different internal calcium channel, regulate calcium release in each of these diverse functions. The essential nature of RyRs is underlined by death at or before birth when RyR expression is defective. Genetic defects in the RyR cause cardiac arrhythmias, malignant hyperthermia and central core disease. RyR function is compromised in heart failure and fatigue. The key role of RyRs makes them a potential therapeutic target, but they are not used as such because of the limited knowledge of the nature and structure of their regulatory sites. Electrical signals from the brain are able to release calcium from internal stores in muscle and initiate muscle contraction by virtue of a physical interaction between two calcium channel proteins, a surface membrane channel and the RyR. The molecular basis of this protein-protein interaction is is not understood and is a subject of this proposal. We will (a) solve the structure of one part of the surface channel that is known to contribute to the protein-protein interaction with the RyR, (b) determine the amino acid residues that interact with each other and (c) evaluate the functional consequences of the the binding of proteins. Understanding more about RyR regulation will pave the way for rational drug design and the eventual use of the RyR as a therapeutic target.Read moreRead less
SPECIFIC MODIFICATION OF SKELETAL MUSCLE RYANODINE RECEPTOR ACTIVITY
Funder
National Health and Medical Research Council
Funding Amount
$411,000.00
Summary
The project will have implications for muscle fatigue, which is a public health issue in an aging population, and for neuromuscular diseases and muscle weakness. The ryanodine receptor (RyR) calcium release channel regulates changes in calcium concentrations inside the muscle cell that are essential for respiration and movement. Defects in expression of RyRs results in death in utero or at birth. The RyR is also important in many other tissues, where it acts either alone or in combination with a ....The project will have implications for muscle fatigue, which is a public health issue in an aging population, and for neuromuscular diseases and muscle weakness. The ryanodine receptor (RyR) calcium release channel regulates changes in calcium concentrations inside the muscle cell that are essential for respiration and movement. Defects in expression of RyRs results in death in utero or at birth. The RyR is also important in many other tissues, where it acts either alone or in combination with a second type of calcium channel, to regulate the changes in the concentrations of calcium ions within the cell, which are essential for a variety of processes including cardiac contraction, vascular constriction, neuronal activity and immune responses. Despite its importance, little is known about the regulation of the RyR channel opening during contraction in skeletal muscle or the mechanisms of ion movement through its pore. It is often difficult to define the specific role of RyRs in intact tissues because of the lack of specific probes for the channel. The RyR is an obvious target for therapeutic drugs to modify muscle contraction, but has not been used as such because of the lack of specific and reversible drugs. Muscle performance is reduced, and fatigue is rapid, in neuromuscular disease. Performance can be improved by variety of drugs like anabolic steroids which unfortunately have additional adverse actions. The aims of the project are (a) to discover more about the regulation of, and ion conduction pathway through, the skeletal muscle RyR channel, (b) to identify compounds that can be used as specific probes for RyR activity and (c) to identify compounds that might in the future provide the basis for development of the RyR as a therapeutic target.Read moreRead less
A Novel Lipidic Adjuvant Carrier System For Vaccination Including Vaccination Via The Oral Route
Funder
National Health and Medical Research Council
Funding Amount
$214,593.00
Summary
We have developed a Lipid-Core-Peptide vaccine adjuvant system, based on the incorporation of lipoamino acids into poly-functional moiety that provides an excellent means for enhancing the antigenicity of a potential peptide-vaccine. As the system contains many variables, which allow substantial modifications to be made, we now wish to fully optimise its structural configuration. A library of spacer-lipoamino acid-poly-functional multiplier systems will be synthesised on solid phase. Model pepti ....We have developed a Lipid-Core-Peptide vaccine adjuvant system, based on the incorporation of lipoamino acids into poly-functional moiety that provides an excellent means for enhancing the antigenicity of a potential peptide-vaccine. As the system contains many variables, which allow substantial modifications to be made, we now wish to fully optimise its structural configuration. A library of spacer-lipoamino acid-poly-functional multiplier systems will be synthesised on solid phase. Model peptide epitopes will be synthesised on these different lipid-core systems and the antibody response will be compared with the response of the model peptide epitopes coupled to conventional vaccine carriers. The Lipid-Core Immunogen constructs including particulate systems will be administered orally as well, followed by measurement of the serum IgG response and the secretory IgA. This novel system can be used for any potential vaccine-peptide epitope and can open a new route to modern vaccination. The specific advantages of these kind of synthetic vaccines include the greater stability of the vaccine, reproducibility, eliminate the use of toxic conventional adjuvants. The key to this system is a novel carrier construct, which is non-toxic and not immunogenic. The system confers immunity with smaller risk of reaction, since it generates antibody production only against the infective microorganism. Vaccination via the oral route is highly desirable since it can overcome many of the disadvantages inherent in administration by injection - e.g. poor patient acceptability, requirement for skilled medical personnel, risk of HIV and other blood-borne diseases, restricted availability and, in cases, stimulation of the wrong type of immunity. Development of vaccines for oral administration will make them much more widely available, permitting self-administration by patients and markedly improving the operation of Public Health vaccination programs, particularly in developing countries.Read moreRead less