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Structure and Function of C. Difficile Toxins

艰难梭菌毒素的结构和功能

基本信息

批准号：
9913462
负责人：
Min Dong
金额：
$ 80.4万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-15 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9913462
关键词：
Accounting Address Affinity Basic Science Binding Biology Bontoxilysin CRISPR/Cas technology Cell model Cells Centers for Disease Control and Prevention (U.S.)Cessation of life Clostridium difficile Clostridium difficile tcdA protein Colitis Collaborations Complement Complex Crystallization Custom Data Developed Countries Development Diarrhea Disease Docking Epithelial Epithelium Exhibits Exotoxins FZD1 gene FZD2 gene Fatty Acids Gastroenteritis Goals Heparitin Sulfate Human Infection Investigation Knowledge Length Lipoprotein (a)Low Density Lipoprotein Receptor Mass Spectrum Analysis Mediating Modeling Molecular Mus Mutagenesis Nonesterified Fatty Acids Organoids Pathogenesis Pathogenicity Pathway interactions Proteins Publishing Receptor Cell Research Role Series Site Structural Models Structure Therapeutic Intervention Toxic effect Toxin Tropism WNT Signaling Pathway Work alpha Toxin antibiotic-associated diarrhea crosslink design experimental study genome wide screen insight interdisciplinary approach member molecular targeted therapies multidisciplinary mutant novel novel therapeutic intervention receptor receptor binding research study small molecule targeted treatment therapeutic development tool translational study

项目摘要

Project Summary Clostridium difficile infection (CDI) is the most common cause of antibiotic-associated diarrhea and gastroenteritis-associated death among developed countries, and it is classified as one of the top three “urgent threats” by the US Centers for Disease Control and Prevention (CDC). The disease associated with CDI is mainly mediated by two homologous exotoxins, TcdA and TcdB. They target and disrupt the colonic epithelium, leading to diarrhea and colitis. Receptor-binding is a critical step in the toxin’s action and largely determine toxin tropisms, and these receptors are also molecular targets for therapeutic interventions. The goal of our proposal is to identify and characterize toxin receptors, establish a structural basis for toxin-receptor recognition, and harness this knowledge to gain a mechanistic understanding of the biology, pathogenesis, and therapy of TcdA and TcdB. We will take a multi-disciplinary approach, bringing together the expertise in toxin structure/function of Dr. Rongsheng Jin’s group with the expertise in toxin receptor identification/pathogenesis of Dr. Min Dong’s group. This proposed work is built on both our published work on identifying Frizzled (FZD) proteins as TcdB receptors, and extensive preliminary data on toxin-receptor interactions. We will focus on three aims: (1) elucidate the structural basis and pathogenic relevance of TcdB-FZD recognition;; (2) understand the structure of TcdB and the influence of FZD binding;; and (3) identify and characterize novel TcdA receptors through a CRISPR/Cas9 mediated genome-wide screens. These proposed studies will provide a comprehensive understanding of toxin-receptor interactions and how they contribute to the toxin biology and pathogenesis of TcdA and TcdB.

项目总结