The botulinum neurotoxins, BoNTs, produced by Clostridium botulinum are among the most potent toxins known to man. The Centers for Disease Control and Prevention (CDC) has classified it as a potential bioweapon, Category A, because of its extreme potency and lethality, its ease of production and transport, and the need for prolonged intensive care among affected persons. This project participates on a collaboration focusing on the various serotypes and subtypes of the toxin with the overall goal of characterizing these variants at the DMA and protein level and developing a deeper understanding of neurotoxin action. We will focus on three major research areas: (1) continuing to deepen our understanding of the cell receptor recognition and binding processes as well as the translocation process by determining the structures of the toxin in complex with cell recognition receptor molecules, (2) developing a detailed understanding on how the recently developed antibodies (Abs), work and how we can then improve them, and (3) using structurebased approaches engineer the next generation broad spectrum diagnostic antibodies (working towards one antibody to recognize multiple toxin subtypes and serotypes). The study will characterize a number of BoNT variants to assess their impact on the development of diagnostics and therapeutics and to understand differences in biological action. In addition to the structures, the project will also produce highly purified protein samples that will be made available to its collaborators and other workers in the biodefense consortium.

Public Health Relevance

We will structurally characterize botulinum neurotoxins (BoNTs);the most potent toxins known to man and classified as potential bio-weapon, category A by CDC. Variants have been identified and antibodies were shown to be ineffective across subtypes. Diagnostics and therapeutics development including the numerous and widely used medical applications that utilize the toxin (e.g., dystonia, chronic pain, neuromuscular disorders) will benefit from a deeper understanding of toxin action.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54AI065359-09
Application #
8462544
Study Section
Special Emphasis Panel (ZAI1-DDS-M)
Project Start
Project End
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
9
Fiscal Year
2013
Total Cost
$273,734
Indirect Cost
$26,301
Name
University of California Irvine
Department
Type
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
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