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Principal Investigator: THOMAS Elliott VAN DYKE
Organization: ADA FORSYTH INSTITUTE, INC.
Fiscal Year: 2021
Award: $463,125
Funding agency: National Institute of Dental and Craniofacial Research
Project Summary
Uncontrolled inflammation is a major impediment to tissue engineering, regeneration and reconstruction of
both diseased and injured tissues resulting in further tissue injury, tissue scarring and fibrosis. Stem cell
activity is disrupted by persistent signals promoting inflammation, whereas specific anti-inflammatory signals
enhance stem cell activity. In successful regeneration, mesenchymal stem cells assume an anti-inflammatory
phenotype. Specialized Proresolving lipid Mediators (SPMS), including Lipoxin A4 (LXA4), attenuate the dental
stem cell inflammatory response. Resolution of inflammation is an active biochemical and metabolic process,
not merely a passive termination of inflammation, mediated by SPMs. SPMs activate wound healing with
tissue regeneration instead of fibrosis and scarring and directly improve bone healing and regeneration,
including in periodontitis. Human periodontal ligament stem cells release SPMs, including lipoxin, to regulate
immunomodulatory and pro-healing properties. Characterizing the biomimetic properties of SPMs in humans
is hampered by a lack of suitable large animal models. There is a critical need for a validated large animal
regeneration model to test therapeutic potential of SPMs for translation to humans. Our goal is to determine
the pathways to regeneration that control local inflammation and enhance mesenchymal stem cell
differentiation into connective tissues, including bone. The Central Hypothesis is that resolution of
inflammation pathways and mediators can promote regeneration of the periodontal organ (bone, cementum
and periodontal ligament) by directing stem cell phenotype, proliferation and differentiation. In this application,
we will use a large animal model to dissect the SPM pathways leading to periodontal ligament stem cell control
of regeneration. In this proposal, we will: 1: Provide direct evidence for SPM production by Yorkshire miniature
pig periodontal ligament stem cells (mpPDLSC) by determining the lipid mediator profile of mpPDLSC; 2:
Determine stem cell function in miniature pig by determining mpPDLSC proliferation and response to SPMs,
and determination of synthetic enzyme expression, signaling pathways and SPM receptor expression, and 3:
Demonstrate SPM enhanced stem cell mediated periodontal regeneration in Miniature Pigs using SPM local
delivery to enhance periodontal regeneration alone or in combination with transplanted, ex vivo expanded
miniature pig stem cells. Results from these studies will advance our practical clinical knowledge of dose and
delivery of lipoxins in tissue regeneration, identify potential new molecular targets, and further develop and
characterize a large animal model to test novel stem cell-based strategies for translation to human oral and
craniofacial tissue regeneration. The research team comprises experts in periodontal regeneration,
biochemistry, and large animal models.
Terms: <15-LOX><15-Lipoxygenase><5,6,15-tri-HETE><5,6,15-triHETE><5,6,15-trihydroxy-7,9,11,13-eicosatetraenoic acid><Address><Alveolodental Ligament><Alveolodental Membrane><Animal Model><Animal Models and Related Studies><Animals><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Antiinflammatories><Antiinflammatory Agents><Arachidonate 15-Lipoxygenase><Arachidonate Omega-6 Lipoxygenase><Arachidonic Acid 15-Lipoxygenase><Attenuated><Biochemical Process><Biochemistry><Biological Chemistry><Biological Mimetics><Biomimetics><Body Tissues><Bone Regeneration><CD59 Antigen><Cell Communication and Signaling><Cell Signaling><Cementum><Chronic Periodontitis><Cicatrix><Clinical><Connective Tissue><Dental><Dental Cementum><Developmental Biology><Diet><Disease><Disorder><Dose><Environment><Family suidae><Fibrosis><Generations><Goals><HRF20><Homologous Restriction Factor 20><Host Defense Mechanism><Human><Immune><Immunes><Immunomodulation><In Vitro><Inflammation><Inflammatory><Inflammatory Response><Intermediary Metabolism><Intracellular Communication and Signaling><Knowledge><LOX><LOX gene><LXA4><LXB4><Lipoxins><MACIF><Mediating><Mediator><Mediator of Activation><Mediator of activation protein><Membrane Attack Complex Inhibition Factor><Membrane Inhibitor of Reactive Lysis><Mesenchymal Progenitor Cell><Mesenchymal Stem Cells><Mesenchymal progenitor><Metabolic Processes><Metabolism><Modern Man><Molecular Target><Mφ><NIDCR><NIDR><National Institute of Dental Research><National Institute of Dental and Craniofacial Research><Natural regeneration><Organ><Pathway interactions><Periodontal Ligament><Periodontal Membrane><Periodontitis><Phenotype><Pigs><Production><Progenitor Cells><Property><Protectin><Publishing><Regeneration><Research><Resolution><Reticulocyte Arachidonate 15-Lipoxygenase><Scars><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Strategic Planning><Suidae><Swine><Testing><Tissue Engineering><Tissues><Transplantation><Wound Repair><analog><antiinflammatory><base><bioengineered tissue><biological signal transduction><bone><bone healing><bone repair><bone wound healing><craniofacial tissue><diets><engineered tissue><enzyme biosynthesis><experiment><experimental research><experimental study><healing><human disease><immune modulation><immune regulation><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><improved><injured><injury to tissue><lipid mediator><lipoxin A4><lipoxin B4><macrophage><man><man's><microbiome><model of animal><model organism><nano particle><nano-sized particle><nanoparticle><nanosized particle><novel><oral tissue><osseous wound healing><pathway><porcine><pre-clinical study><preclinical study><progenitor cell function><progenitor cell proliferation><programs><receptor expression><reconstruction><regenerate><regenerate bone><regenerate new tissue><regenerate tissue><regenerating damaged tissue><regenerating tissue><regeneration model><regenerative><regenerative model><response><stem cell based therapy><stem cell biology><stem cell differentiation><stem cell function><stem cell mediated therapy><stem cell proliferation><stem cell therapeutics><stem cell therapy><stem cell treatment><stem cell-based treatment><stem cells><suid><synthetic enzyme><therapeutic evaluation><therapeutic testing><tissue injury><tissue regeneration><tissue renewal><tissue specific regeneration><translation strategy><translation to humans><translational approach><translational strategy><transplant><wound healing><wound resolution>