Characteristics of Botulinum Neurotoxins that determine potency
决定效力的肉毒杆菌神经毒素的特征
基本信息
- 批准号:10539300
- 负责人:
- 金额:$ 63.6万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-01-18 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAmazeAmino Acid SubstitutionAmino AcidsAnimalsAreaBindingBiologicalBiological AssayBiological ProductsBotulinum ToxinsBotulismC-terminalCCRL2 geneCaringCategoriesCell modelCellsCessation of lifeCharacteristicsChimera organismClassificationDataDevelopmentDiseaseDoseElementsEngineeringEstheticsGangliosidesHumanImmunologicsIn VitroIndividualIntoxicationInvestigationKineticsKnowledgeLaboratoriesLightMapsMedicalMedicineMembraneModelingMolecularMusMutagenesisMutateMutationN-terminalNeuromuscular DiseasesNeuronsParalysedPathogenicityPathologicPathologyPatientsPharmacologic SubstancePropertyProtein FamilyProteinsReceptor CellRecombinantsResearchRodentRoleSerotypingSeverity of illnessStructural ModelsSupportive careSystemTestingTherapeuticTimeToxic effectToxinVariantantitoxinbasebeta-Lactamasebioweaponcostdigitalexperimental studyholotoxinsimprovedin vivoinsightmouse modelnervous system disordernovelnovel therapeuticspathogenpharmacologicreceptorreceptor bindingrespiratorytraffickinguptakeweapons
项目摘要
Abstract
Botulinum Neurotoxins (BoNTs) are a large family of protein toxins and are of great significance due to their
extreme potency and the severity of the disease they cause in humans and animals. Botulism is a
neuroparalytic disease of long duration, lasting up to several months. Without proper medical care, naturally
occurring botulism is lethal in up to 50% of cases, and even with respiratory and other supportive care and
antitoxin administration, up to 5 % of patients die. While naturally occurring botulism is rare, BoNTs are
classified as a Tier 1 Category A Select Agent due to their threat as potential bioterrorist weapons. Amazingly,
BoNTs are also widely used in medicine to treat more than 100 neuromuscular disorders and for aesthetic
purposes. BoNTs are immunologically divided into 7 serotypes, which are further subdivided into subtypes.
Today, 100s of BoNT variants have been identified by sequencing efforts, but only few have been investigated
at the protein level. It is noteworthy that out of all the BoNT variants only two (BoNT/A1 and /B1) are currently
used as therapeutics, and studies examining properties of other variants are infrequent. Our research groups
have determined for the first time that subtypes within the BoNT/A serotype have distinct biologic properties,
including cell entry kinetics, duration of action, cell and mouse toxicity, and immunological variations. This
RO1 project proposes to determine on a molecular and structural level the mechanisms underlying these
unique properties of A subtypes and the chimeric BoNT/FA. Specifically, this project will investigate the
mechanisms underlying the shorter duration of action of BoNT/A3, the faster and more efficient cell entry by
BoNT/A2, /A6, and /FA, the 1,000 fold lower toxicity of BoNT/A4. Our collaborative efforts are unique in this
area, as we are able to combine detailed mechanistic studies on subdomains with cell-based and in vivo
studies on the holotoxin level. The Barbieri lab will use structural modeling to guide mutagenesis studies on
functional domains of BoNTs and investigate mechanisms of receptor binding and cell trafficking using
neuronal cell models. The Johnson/Pellett laboratory will utilize these data to create targeted holotoxin
constructs in their native hosts and conduct detailed investigations in various rodent and human cell models.
Finally, based on the data from these studies, select holotoxin constructs will be investigated in mice to
determine pathologic and pharmacologic consequences of structural alterations. Using this approach, we will
investigate a large number of amino acid substitutions in functional domain studies and select specific
alterations for the more effort- and cost-intensive construction of recombinant holotoxins. By utilizing several
cell models before conducting in vivo studies, we are able to reduce the number of required animals and also
use human specific models. Finally, the combination of in vitro, cell-based, and in vivo studies will provide
novel insight into the mechanisms underlying the observed pathologic and pharmacologic properties of these
toxins.
摘要
项目成果
期刊论文数量(7)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Endogenous CRISPR-Cas Systems in Group I Clostridium botulinum and Clostridium sporogenes Do Not Directly Target the Botulinum Neurotoxin Gene Cluster.
- DOI:10.3389/fmicb.2021.787726
- 发表时间:2021
- 期刊:
- 影响因子:5.2
- 作者:Wentz TG;Tremblay BJM;Bradshaw M;Doxey AC;Sharma SK;Sauer JD;Pellett S
- 通讯作者:Pellett S
Resolution of Two Steps in Botulinum Neurotoxin Serotype A1 Light Chain Localization to the Intracellular Plasma Membrane.
- DOI:10.3390/ijms222011115
- 发表时间:2021-10-15
- 期刊:
- 影响因子:5.6
- 作者:Gardner A;Tepp WH;Bradshaw M;Barbieri JT;Pellett S
- 通讯作者:Pellett S
Posttranslational Regulation of Botulinum Neurotoxin Production in Clostridium botulinum Hall A-hyper.
- DOI:10.1128/msphere.00328-21
- 发表时间:2021-08-25
- 期刊:
- 影响因子:4.8
- 作者:Inzalaco HN;Tepp WH;Fredrick C;Bradshaw M;Johnson EA;Pellett S
- 通讯作者:Pellett S
Botulinum Neurotoxin A4 Has a 1000-Fold Reduced Potency Due to Three Single Amino Acid Alterations in the Protein Receptor Binding Domain.
- DOI:10.3390/ijms24065690
- 发表时间:2023-03-16
- 期刊:
- 影响因子:5.6
- 作者:
- 通讯作者:
How Botulinum Neurotoxin Light Chain A1 Maintains Stable Association with the Intracellular Neuronal Plasma Membrane.
- DOI:10.3390/toxins14120814
- 发表时间:2022-11-22
- 期刊:
- 影响因子:4.2
- 作者:Gardner AP;Barbieri JT;Pellett S
- 通讯作者:Pellett S
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Joseph T Barbieri其他文献
Joseph T Barbieri的其他文献
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{{ truncateString('Joseph T Barbieri', 18)}}的其他基金
Characteristics of Botulinum Neurotoxins that determine potency
决定效力的肉毒杆菌神经毒素的特征
- 批准号:
10326384 - 财政年份:2019
- 资助金额:
$ 63.6万 - 项目类别:
Therapeutic Delivery Platforms against Botulism
针对肉毒杆菌中毒的治疗递送平台
- 批准号:
8366528 - 财政年份:2012
- 资助金额:
$ 63.6万 - 项目类别:
Therapeutic Delivery Platforms against Botulism
针对肉毒杆菌中毒的治疗递送平台
- 批准号:
8468641 - 财政年份:2012
- 资助金额:
$ 63.6万 - 项目类别:
Characterization of botulinum neurotoxin A subtypes
肉毒杆菌神经毒素 A 亚型的表征
- 批准号:
9542546 - 财政年份:2012
- 资助金额:
$ 63.6万 - 项目类别:
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