The proposed research aims to investigate the regulatory mechanism used by LytTR Regulatory Systems (LRS) as well as explore a cell death pathway triggered by these systems in Streptococcus mutans. LRS are a newly described gene regulatory system that consists of a LytTR family transcription regulator and putative membrane protein inhibitor that antagonizes the function of this regulator. The goals of this project will b achieved in three aims by: 1) determining the inhibitory mechanism employed by LRS membrane proteins;2) characterizing the components downstream of LRS responsible for mediating cell death;and 3) developing a therapeutic model of the LRS cell death pathway. 1) To determine how LRS membrane proteins function as inhibitors, we will examine three different mechanisms of inhibition: protein stability, posttranslational modification, and sequestration. Protein-protein interaction studies will determine whether LRS membrane proteins exert their function directly. 2) To characterize the mediators of cell death, we will use genetic techniques to determine the genes/pathways required for the lethal phenotype of a mutant strain that constitutively activates the LRS cell death pathway. 3) To assess the therapeutic potential of the LRS cell death pathway, we will test a positive feedback regulatory model between three S. mutans LRS. An inducible cell death system will be tested for functionality in in vitro and in vivo model systems. The goal of these studies is to create a model system for LRS function in Gram positive bacteria and to determine the potential utility of the LRS cell death pathway in inhibitin preformed biofilm communities.

Public Health Relevance

Dental caries is one of the most common infectious diseases in humans and is largely correlated with the overgrowth of Streptococcus mutans. These studies aim to reduce the prevalence of S. mutans and reduce the caries burden by examining a gene regulatory system that can used to inhibit the growth of S. mutans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
1R01DE022083-01A1
Application #
8500984
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Lunsford, Dwayne
Project Start
2013-09-13
Project End
2017-08-31
Budget Start
2013-09-13
Budget End
2014-08-31
Support Year
1
Fiscal Year
2013
Total Cost
$370,000
Indirect Cost
$120,000
Name
University of Oklahoma Health Sciences Center
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
878648294
City
Oklahoma City
State
OK
Country
United States
Zip Code
73117