R01DE031946

Amelogenin Nanoribbons in Enamel Development and Engineering

Enamel is the only epithelial derived tissue that mineralizes. It develops in an extracellular matrix secreted by highly specialized epithelial cells, the ameloblasts, which synthesize a host of specific matrix proteins with little homology to any other known proteins. Amelogenin is by far the largest constituent of the developing enamel matrix (DEM), comprising ~90% of all secreted protein. Amelogenin's primary structure encodes a series of critical functions of the DEM that ultimately allow for control over the uniaxial growth of apatite nanofibers and their three-dimensional organization into a stiff, hard, and fracture-resistant tissue optimized for mastication and integration with the underlying dentin.

Previously, we have demonstrated the biological significance of the amyloid-like character of amelogenin, which allows the protein to adopt β-sheet structure and to self-assemble into nanoribbons (Amel-NRs) that guide the growth of mineral ribbons. Based on this data, a new model of enamel biomineralization founded on the activation of the mineralization process by the enzymatic cleavage of amelogenin by matrix metalloprotease-20 (MMP20) has been proposed and will be further evaluated in this application.

We have hitherto shown that removal of the hydrophilic C-terminal domain allowed an acidic polymer to interact with Amel-NRs, thereby initiating the deposition of an amorphous calcium phosphate (ACP) layer. Subsequently, ACP transformed into crystalline apatite in the form of ribbon-like mineral about 15-20 nm wide that followed the morphology of the Amel-NRs. The sequential process of biomineralization observed in our in vitro model correlates with biological events of tissue mineralization and reinforces emerging concepts of biomineralization not only valid to enamel but other hard tissues. Such concepts include: a) biomineralization is regulated by proteolysis; b) presence of a carrier-protein that acts as a process-directing agent and delivers mineral ions to a self-assembled protein framework; c) carrier-protein interactions produce amorphous mineral deposits onto the protein framework; d) the supramolecular structure of the organic phase directs the phase transformation into defined crystal habits by oriented crystallization.

In continuation of previous studies, we propose to identify constituents of the DEM that are critical for the templated growth of crystalline apatite nanofibers in association with the protein nanoribbons. By determining the three-dimensional structure of Amel-NRs at near-atomic resolution, further functional domains will be identified and associated with critical molecular and structural mechanisms in enamel formation. Ultimately, we plan to use the unique ability of Amel-NRs to direct the fibrous growth of apatite and synthesize nanomaterials through hierarchical design at the micro- and nanometer length scale.

San Francisco Regents Of The University Of California

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, INCLUDING SMALL BUSINESS RESEARCH THROUGH THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) AND SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAMS 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 SUPPORT 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 SUPPORT 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 SUPPORT 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. 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 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]

San Francisco, California 941432210 United States

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

Amendment Since initial award the total obligations have increased 380% from $697,772 to $3,352,519.