R01DE029775

A Novel Mechanism of Virulence Control in Porphyromonas gingivalis - Abstract

Porphyromonas gingivalis is a major pathogen of severe adult periodontitis, a polymicrobial disease caused by the coordinated action of a complex microbial community that leads to inflammation of tissues supporting the teeth.

A central hurdle limiting progress in periodontal disease research is the paucity of information detailing microbial signals that correlate with clinical progression at a site from health to disease. Filling this void, we recently reported metatranscriptome findings of the microbial community from human clinical samples during periodontal disease progression and discovered that CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)-associated proteins in the periodontopathogen P. gingivalis were highly up-regulated only at those sites that progressed.

CRISPR-Cas systems are used by bacteria to prevent foreign DNA incorporation, as occurs with a viral attack. The goal of this research program is to understand the role that CRISPR-Cas systems have on virulence determinants of important periodontopathogens during disease progression. A comprehensive analysis of the mutants will provide information required to increase our understanding of not only CRISPR gene function but also the contribution of these novel genes to virulence.

To this end, we propose the following specific aims:

Aim 1: Identify targeted endogenous genes by comparing transcriptome profiles of the wild-type and the mutants growing intracellularly.

Aim 2: Determine the impact of CRISPR-associated genes on the innate immune host responses to P. gingivalis.

Aim 3: Determine the role of CRISPR-Cas genes in the pathogenicity of P. gingivalis.

We expect that this knowledge will facilitate the development of targeted approaches to prevent and treat periodontitis by inhibiting specific Cas proteins essential for virulence. Such results will fundamentally advance our understanding of the role that such systems have in the metabolism of periodontal pathogens besides their traditional role assigned as a mechanism of protection against foreign DNA.

We believe that the team we have assembled for this project has all the qualifications to successfully accomplish the goals proposed in the present application.

University Of Florida

NIDCR EXTRAMURAL RESEARCH PROVIDES RESEARCH FUNDS TO SUPPORT BASIC, TRANSLATIONAL, AND CLINICAL RESEARCH IN DENTAL, ORAL, AND CRANIOFACIAL HEALTH AND DISEASE THROUGH GRANTS, COOPERATIVE AGREEMENTS, AND CONTRACTS THAT SUPPORT SCIENTISTS WORKING IN INSTITUTIONS THROUGHOUT THE UNITED STATES AND INTERNATIONALLY. EXTRAMURAL PROGRAMS PLAN, DEVELOP, AND MANAGE SCIENTIFIC PRIORITIES THROUGH PORTFOLIO ANALYSES AND CONSULTATION WITH STAKEHOLDERS, ENCOURAGING THE MOST PROMISING DISCOVERIES AND EMERGING TECHNOLOGIES FOR RAPID TRANSLATION TO CLINICAL APPLICATIONS. THE INTEGRATIVE BIOLOGY AND INFECTIOUS DISEASES PROGRAMS SUPPORTS BASIC AND TRANSLATIONAL RESEARCH PROGRAMS ON ORAL MICROBIOLOGY, SALIVARY BIOLOGY AND IMMUNOLOGY, ORAL AND SALIVARY GLAND CANCERS, NEUROSCIENCE OF OROFACIAL PAIN AND TEMPOROMANDIBULAR DISORDERS, MINERALIZED TISSUE PHYSIOLOGY, DENTAL BIOMATERIALS, AND TISSUE ENGINEERING AND REGENERATIVE MEDICINE. THE BRANCH AIMS TO ACCELERATE PROGRESS IN BASIC AND TRANSLATIONAL RESEARCH IN THESE AREAS, AND FURTHER STIMULATE THE DISCOVERY PIPELINE BASED ON CLINICAL NEEDS. THE TRANSLATIONAL GENOMICS RESEARCH PROGRAMS SUPPORTS BASIC AND TRANSLATIONAL RESEARCH IN GENETICS, GENOMICS, DEVELOPMENTAL BIOLOGY, AND DATA SCIENCE TOWARD THE GOAL OF IMPROVING DENTAL, ORAL, AND CRANIOFACIAL HEALTH. THE FOCUS IS ON DECIPHERING THE GENETIC, MOLECULAR, AND CELLULAR MECHANISMS UNDERLYING DENTAL, ORAL, AND CRANIOFACIAL DEVELOPMENT AND ANOMALIES. THE BEHAVIORAL AND SOCIAL SCIENCES RESEARCH PROGRAMS SUPPORTS BASIC AND APPLIED RESEARCH TO PROMOTE ORAL HEALTH, TO PREVENT ORAL DISEASES AND RELATED DISABILITIES, AND TO IMPROVE MANAGEMENT OF CRANIOFACIAL CONDITIONS, DISORDERS, AND INJURY. THE PROGRAM PRIORITIZES MECHANISTIC RESEARCH THAT CONTRIBUTES TO A CUMULATIVE SCIENCE OF BEHAVIOR CHANGE, TO MAXIMIZE THE RIGOR, RELEVANCE, AND DISSEMINATION OF EFFICACIOUS BEHAVIOR CHANGE INTERVENTIONS. THE CLINICAL RESEARCH PROGRAMS SUPPORTS PATIENT-ORIENTED, POPULATION, AND COMMUNITY BASED RESEARCH AIMED AT IMPROVING THE DENTAL, ORAL, AND CRANIOFACIAL HEALTH OF THE NATION. THE CENTER FOCUSES ON A VARIETY OF DISEASES AND CONDITIONS THROUGH CLINICAL TRIALS, EPIDEMIOLOGIC STUDIES, PRACTICE-BASED RESEARCH, THE HIV/AIDS AND ORAL HEALTH PROGRAM, AND STUDIES OF ORAL HEALTH DISPARITIES AND INEQUITIES IN ALL AREAS OF NIDCR PROGRAMMATIC INTEREST. THE PROGRAM ENCOURAGES INVESTIGATIONS THAT HAVE THE POTENTIAL TO TRANSLATE FINDINGS INTO EVIDENCE-BASED CLINICAL APPLICATIONS. THE RESEARCH TRAINING AND CAREER DEVELOPMENT EXTRAMURAL PROGRAMS SPAN THE CAREER STAGES OF SCIENTISTS, SUPPORTING RESEARCH TRAINING AND CAREER DEVELOPMENT FOR PHD AND DUAL DEGREE DDS/DMD-PHD STUDENTS, POSTDOCTORAL SCHOLARS, AND EARLY CAREER, MIDCAREER, AND ESTABLISHED INVESTIGATORS. THE PROGRAMS MANAGE SUPPORT FOR FELLOWSHIPS, RESEARCH TRAINING GRANTS, CAREER DEVELOPMENT AND CAREER TRANSITION AWARDS, NIH LOAN REPAYMENT AWARDS, AND DIVERSITY SUPPLEMENTS TO SUPPORT RESEARCH EXPERIENCES FOR HIGH SCHOOL STUDENTS THROUGH INVESTIGATORS. NIDCR PARTICIPATES IN THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) AND SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAMS. THE SBIR PROGRAM IS INTENDED TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.THE STTR PROGRAM IS INTENDED TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. EXTRAMURAL PROGRAMS ARE ACCOUNTABLE FOR THE EFFICIENT AND EFFECTIVE USE OF TAXPAYER FUNDS TO SUPPORT RESEARCH ON DENTAL, ORAL, AND CRANIOFACIAL DISEASES AND DISORDERS AND IMPROVING THE ORAL HEALTH OF ALL AMERICANS. EXTRAMURAL PROGRAMS SUPPORT RESEARCH AND RESEARCH TRAINING TO ESTABLISH THE FOUNDATION FOR SCIENTIFIC DISCOVERIES THAT INCLUDE TRANSPARENT AND RIGOROUS PLANNING, PRIORITY SETTING, CONTINUOUS AND CONSISTENT REVIEWS OF PROGRESS, AND FOCUS ON THE DEVELOPMENT OF A DIVERSE, HIGHLY SKILLED, AND NIMBLE WORKFORCE THAT CAN RAPIDLY RESPOND TO SCIENTIFIC BREAKTHROUGHS AND PUBLIC HEALTH CHALLENGES. EXTRAMURAL PROGRAMS ARE ACCOUNTABLE FOR THE EFFICIENT AND EFFECTIVE USE OF TAXPAYER FUNDS TO SUPPORT RESEARCH ON DENTAL, ORAL, AND CRANIOFACIAL DISEASES AND EMPLOY EVALUATION DOMAINS, FROM NEEDS ASSESSMENT AND STRATEGIC PLANNING TO IMPLEMENTATION AND PROCESS EVALUATION, PERFORMANCE MEASUREMENT, AND OUTCOMES AND IMPACT ANALYSIS TO EVALUATE STRATEGIC OBJECTIVES

93.121 - Oral Diseases and Disorders Research

National Institute of Dental and Craniofacial Research (NIDCR) [HHS - NIH]

Gainesville, Florida 326115500 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 380% from $692,868 to $3,328,558.