The long-term objective of the proposed research is to determine the mechanism of action of botulinum neurotoxin, the botulinum binary toxin, and tetanus toxin. This long-term objective is seen as a prelude to research in experimental therapeutics. Formally speaking, there is no cure for patients who are poisoned with any of the clostridial toxins. Clinical care is limited to providing supportive therapy while the nervous system overcomes the effects of poisoning. It is anticipated that a determination of the mechanism of action of the toxins will reveal testable strategies for developing better and possibly curative treatments. A model has been proposed to account for the poisoning effects of the clostridial toxins. This model envisions an extracellular binding step, a membrane translocation step, and an intracellular poisoning step. The proposed research aims to identify those regions of the toxin molecules that account for these three steps, and furthermore to clarify the cellular and subcellular mechanisms associated with the three steps. Most of the research will focus on the isolated neuromuscular junction (phrenic nerve-hemidiaphragm preparation). A variety of pharmacological agents (e.g., monoclonal antibodies, lysosomotropic agents) and biochemical techniques (e.g., fractionation of polypeptides) will be used to modify toxin action. By virtue of locating regions in the toxin molecules that are vulnerable to inactivation and by virtue of characterizing stages in the neuroparalytic process that are subject to manipulation, the proposed work should indicate ways to develop clinically useful drugs.
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