R01DE031439

Cartilage and bone of the lower jaw in development and disease - Project Summary

The lower jaw evolved as a structure composed of many bones. The largest of which, the dentary, persists as a single lower jawbone in modern mammals, and is referred to as the mandible in humans. Mandibular disorders, often resulting in small jaws, are among the most common human birth defects. These disorders can dramatically affect quality of life and are often associated, or compound problems with airway obstruction, speech, and feeding.

During embryogenesis, development of the mandible is preceded by and associated with a tubular cartilage rod called Meckel's cartilage (MC). Anomalies of MC have been associated with mandibular disorders. Development of MC in modern mammals is complex: the anterior part contributes to the formation of the mandibular symphysis, its posterior part forms cartilages that mineralize endochondrally to form two middle ear bones, and the posterior half of the middle region forms ligaments. Less is known about the anterior half of the middle region of MC, which is transient, present during a small window of embryonic development before it disappears.

Established assessments describe MC as a template for the formation of the mandible, but evidence of this is lacking, and little is known of the relationship between the midportion of MC and mandibular mineralization, size, and shape or the processes of MC growth in length, perichondrial ossification, and disappearance of MC.

We present data demonstrating that MC does not serve as a template in the way cartilaginous models function in endochondral ossification and hypothesize a new role for the mid portion of MC in determining mandibular length, mineralization of the perichondrium, mineralization of the mandible, and its disappearance. Because our findings challenge the traditional role of MC, we have designed this project to validate the developmental events that take place as the midportion of MC disappears and the mandible forms through a detailed analysis of four processes:

1) Initiation and growth in length of MC;
2) Mineralization of MC perichondrium;
3) Mineralization of the mandible; and
4) Disappearance of MC.

Our approach is based on knowledge we have gained through preliminary investigations of these processes occurring at different times along the length of MC and spanning the buccal to lingual aspects of the interior of MC. We couple 3D imaging with tissue and cellular analyses of embryonic mutant Sox9Flox/Flox;Col2a1-CreERT and Sox9Flox/Flox mice to precisely define the changing cellular dynamics of the lower jaw in developmental time and anatomical space.

These data are used in turn to inform our RNA-seq analyses of the developing MC and mandible directed at recovering the underlying transcriptome by differential gene expression, pathway, and network analyses. We plan cell lineage tracing experiments to determine the fate of cells from the intermediate region of MC, those that initiate MC perichondrial mineralization, and mandible mineralization.

Our integrative approach is designed to bring new understanding to lower jaw development and open novel research areas to advance strategies for bone repair, regeneration, and prevention in mandibular disease.

The Pennsylvania State University

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]

University Park, Pennsylvania 16802 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 290% from $788,094 to $3,073,416.