MECHANISMS OF TRANSMITTER SECRETION AT SYMPATHETIC NERVE VARICOSITIES
Funder
National Health and Medical Research Council
Funding Amount
$438,707.00
Summary
The mechanism by which quantal packets of transmitter are secreted from release sites called varicosities on sympathetic nerve terminals can now be taken to the molecular level, given the new techniques which we have introduced to solve this problem. There are two main facets to the problem. The first of these involves the question of how proteins involved in controlling the regulated secretion or exocytosis of the quantal packets of transmitter carry out this function. These proteins (syntaxin, ....The mechanism by which quantal packets of transmitter are secreted from release sites called varicosities on sympathetic nerve terminals can now be taken to the molecular level, given the new techniques which we have introduced to solve this problem. There are two main facets to the problem. The first of these involves the question of how proteins involved in controlling the regulated secretion or exocytosis of the quantal packets of transmitter carry out this function. These proteins (syntaxin, synaptobrevin, SNAP25 and synaptotagmin) together with a calcium channel are complexed with a docked synaptic vesicle containing a quantum of transmitter in a module of secretion appropriately called a secretosome. The leading questions here are to determine if only a single secretosome participates in transmitter release on the arrival of a nerve impulse, whether the number of these secretosomes in a varicosity determines its probability for secretion of a quantum, and fundamentally, how do the proteins within the secretosome cooperate to trigger exocytosis when there is sufficient calcium influx through the secretosome-associated calcium channel following the impulse. The other problem concerns the mechanism of removal of calcium from the varicosity once it has entered through the channels, This calcium can have considerable affects on the extent to which secretosomes participate in secretion with subsequent impulses. Furthermore, this influx of calcium can be modulated for subsequent impulses by transmitter released by the first impulse. The present research will solve these problems, providing a molecular description of secretion from single sympathetic varicosities.Read moreRead less
Recombinant Bacteria Expressing Oligosaccharide Receptor Mimics For Prevention Of Enteric Infections
Funder
National Health and Medical Research Council
Funding Amount
$451,056.00
Summary
Gastrointestinal infectious diseases kill more than 3 million people each year. The principal microbial pathogens responsible for these infections are known to exploit oligosaccharides on the surface of host cells as receptors for ahesins or toxins. We have developed (and patented) a novel anti-infective strategy, based on mimicry of oligosaccharide receptors for toxins and adhesins produced by enteric pathogens on the surface of harmless carrier bacteria. Oral administration of such recombinant ....Gastrointestinal infectious diseases kill more than 3 million people each year. The principal microbial pathogens responsible for these infections are known to exploit oligosaccharides on the surface of host cells as receptors for ahesins or toxins. We have developed (and patented) a novel anti-infective strategy, based on mimicry of oligosaccharide receptors for toxins and adhesins produced by enteric pathogens on the surface of harmless carrier bacteria. Oral administration of such recombinant probiotics has the potential to prevent enteric infections by binding and neutralizing toxins in the gut lumen and by blocking adherence of the pathogen to intestinal epithelial cells. As a prototypic example, we have developed a bacterium capable of preventing the serious consequences of Shiga toxigenic Escherichia coli (STEC) infections; this agent binds Shiga toxin with very high efficiency and is 100% protective in animal models. The strategy has very broad applications, however, and receptors for virtually any pathogen can be mimicked by expression of appropriate glycosyl transferases in a suitable harmless host bacterium. This proposal involves extension of our existing work to develop therapeutic agents for other important life threatening diarrhoeal diseases including cholera, travellers' diarrhoea, dysentery, antibiotic-associated colitis, rotavirus, etc.Read moreRead less
Role Of Microbiota In The Developing Enteric Nervous System
Funder
National Health and Medical Research Council
Funding Amount
$661,979.00
Summary
The correct development of neurons in the gut is vital for digestive functions. This project will provide novel insights into how environmental factors such as the bacteria that reside in the gut and changes in diet affect maturation of the gut’s nervous system. The data will improve knowledge of the effects of widely used antibiotics and probiotics, which will facilitate strategies to improve human health and quality of life.