R37AI095755
Project Grant
Overview
Grant Description
Structural mechanisms of Clostridioides difficile pathogenesis - Summary
Clostridioides difficile is a gram-positive, spore-forming anaerobe that infects the colon, causing a range of human disease including diarrhea, pseudomembranous colitis, and toxic megacolon.
The United States Centers for Disease Control reports that, in 2017, there were 223,900 estimated cases of C. difficile infection (CDI) in hospitalized patients in the United States with an estimated 12,800 deaths.
The incidence of community-acquired CDI is also common making C. difficile a significant public health concern.
The bacterium makes a toxin, TCDB, which is responsible for the majority of CDI symptoms.
The goal of the proposed project is to define the structural basis and physiologic consequences of TCDB binding to receptor proteins on the host cell surface.
In Aim 1, we will define the structures and key residues involved in TCDB-receptor interactions using a combination of structural biology, mutagenesis, and quantitative binding approaches.
We will use this information to generate C. difficile strains with defined mutations in TCDB receptor binding sites.
In Aim 2, we will evaluate the cellular tropism of the toxin in the context of a human explant intoxication model, taking advantage of significant technological advances in high resolution light microscopy imaging.
These studies will be paired with mechanistic studies in a novel cellular model of TCDB intoxication as well as the mouse model of CDI.
Collectively, these studies will define the physiologic consequences associated with defined TCDB-receptor interactions and are expected to provide a mechanistic framework for advancing novel therapeutic and CDI prevention strategies.
Clostridioides difficile is a gram-positive, spore-forming anaerobe that infects the colon, causing a range of human disease including diarrhea, pseudomembranous colitis, and toxic megacolon.
The United States Centers for Disease Control reports that, in 2017, there were 223,900 estimated cases of C. difficile infection (CDI) in hospitalized patients in the United States with an estimated 12,800 deaths.
The incidence of community-acquired CDI is also common making C. difficile a significant public health concern.
The bacterium makes a toxin, TCDB, which is responsible for the majority of CDI symptoms.
The goal of the proposed project is to define the structural basis and physiologic consequences of TCDB binding to receptor proteins on the host cell surface.
In Aim 1, we will define the structures and key residues involved in TCDB-receptor interactions using a combination of structural biology, mutagenesis, and quantitative binding approaches.
We will use this information to generate C. difficile strains with defined mutations in TCDB receptor binding sites.
In Aim 2, we will evaluate the cellular tropism of the toxin in the context of a human explant intoxication model, taking advantage of significant technological advances in high resolution light microscopy imaging.
These studies will be paired with mechanistic studies in a novel cellular model of TCDB intoxication as well as the mouse model of CDI.
Collectively, these studies will define the physiologic consequences associated with defined TCDB-receptor interactions and are expected to provide a mechanistic framework for advancing novel therapeutic and CDI prevention strategies.
Funding Goals
NOT APPLICABLE
Grant Program (CFDA)
Awarding / Funding Agency
Place of Performance
Nashville,
Tennessee
37203
United States
Geographic Scope
Single Zip Code
Related Opportunity
Analysis Notes
Amendment Since initial award the End Date has been extended from 04/30/26 to 05/31/31 and the total obligations have increased 521% from $518,562 to $3,222,360.
Vanderbilt University Medical Center was awarded
C. difficile TCDB Pathogenesis: Structural Mechanisms
Project Grant R37AI095755
worth $3,222,360
from the National Institute of Allergy and Infectious Diseases in May 2011 with work to be completed primarily in Nashville Tennessee United States.
The grant
has a duration of 20 years and
was awarded through assistance program 93.855 Allergy and Infectious Diseases Research.
The Project Grant was awarded through grant opportunity NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed).
Status
(Ongoing)
Last Modified 6/22/26
Period of Performance
5/15/11
Start Date
5/31/31
End Date
Funding Split
$3.2M
Federal Obligation
$0.0
Non-Federal Obligation
$3.2M
Total Obligated
Activity Timeline
Transaction History
Modifications to R37AI095755
Additional Detail
Award ID FAIN
R37AI095755
SAI Number
R37AI095755-2152858622
Award ID URI
SAI UNAVAILABLE
Awardee Classifications
Nonprofit With 501(c)(3) IRS Status (Other Than An Institution Of Higher Education)
Awarding Office
75NM00 NIH National Institute of Allergy and Infectious Diseases
Funding Office
75NM00 NIH National Institute of Allergy and Infectious Diseases
Awardee UEI
GYLUH9UXHDX5
Awardee CAGE
7HUA5
Performance District
TN-05
Senators
Marsha Blackburn
Bill Hagerty
Bill Hagerty
Budget Funding
| Federal Account | Budget Subfunction | Object Class | Total | Percentage |
|---|---|---|---|---|
| National Institute of Allergy and Infectious Diseases, National Institutes of Health, Health and Human Services (075-0885) | Health research and training | Grants, subsidies, and contributions (41.0) | $1,037,124 | 100% |
Modified: 6/22/26