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Principal Investigator: Anne George
Organization: UNIVERSITY OF ILLINOIS AT CHICAGO
Fiscal Year: 2024
Award: $487,987
Funding agency: National Institute of Dental and Craniofacial Research
For dentin repair or regeneration, it is important to have the timely appearance of blood vessels.
Therefore, tissue-engineering strategies to regenerate the dentin-pulp complex require
establishment of vasculature to deliver oxygen, nutrients, hormones, immune cells, minerals
and also help in clearing cellular debris and metabolic waste products during the inflammatory
and regenerative phases of healing. DMP1 (dentin matrix protein1) is a key regulatory protein in
bone and dentin mineralization. We first demonstrated that it has a regulatory role in the
regulation of hydroxyapatite nucleation and growth in the extracellular matrices of bone and
dentin. Subsequently, we demonstrated that DMP1 was localized in the nucleus of
preosteoblasts and preodontoblasts and thus served as a signaling molecule and promoted the
differentiation of these precursor cells. Recently we discovered that DMP1 can stimulate the
release of intracellular calcium in preosteoblasts and preodontoblasts. Depletion of intracellular
calcium from the endoplasmic reticulum leads to ER stress. Cells cope with ER stress by
activating the “Unfolded protein response” (UPR). One of our recent observations is that DMP1
stimulation can promote the secretion of VEGF and other pro-angiogenic factors. Therefore, we
hypothesize that ER stress activated by DMP1 functions to promote the transformation of adult
stem cells such as dental pulp stem cells to endothelial cells and thereby promote
vasculogenesis. In order to determine the mechanism by which DMP1 promotes
vasculogenesis, we will examine the UPR signaling pathway. The UPR is initiated by three ER
transmembrane proteins, of which our preliminary data show that DMP1 stimulation activated
the ATF6 (Activating Transcription Factor 6) arm of the UPR. Accordingly, here we propose to
study the mechanism by which ATF6 mediate transcriptional regulation of VEGF under ER
stress. During dentin repair and regeneration, a major challenge is the maintenance of cell
viability which depends on the availability of a functional vascular system. Accordingly, we will
test the in-vivo vasculogenic competence and therapeutic potential of DMP1 in an in vivo pulp
regeneration model.
Understanding the complex functions of DMP1 could be valuable to develop therapies for
fracture repair in bone or in the tooth to restore lost, damaged or diseased dentin-pulp
complex.
Terms: <3-D><3-D Imaging><3-Dimensional><3D><3D imaging><7B4 Antigen><7B4 protein><ATF6><ATF6 gene><Activating Transcription Factor 6><Adsorption><Angiogenesis Factor><Angiogenic Factor><Angiogenic Proteins><Appearance><Assay><Basal Transcription Factor><Basal transcription factor genes><Basic Fibroblast Growth Factor><Basic Fibroblast Growth Factor Gene><BiP gene><BiP protein><Binding><Bioassay><Biological Assay><Blood Vessels><Body Tissues><Bone Matrix><CD144 Antigen><CD31><Calcium><Cell Body><Cell Communication and Signaling><Cell Function><Cell Growth and Maintenance><Cell Growth in Number><Cell Maintenance><Cell Multiplication><Cell Nucleus><Cell Physiology><Cell Process><Cell Proliferation><Cell Signaling><Cell Surface Receptors><Cell Survival><Cell Viability><Cell-Extracellular Matrix><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cellular Proliferation><Cellular Stress><Cellular Stress Response><Cold-Insoluble Globulins><Collagen><Competence><Complex><Complex Mixtures><Confocal Microscopy><D-Glucose><Data><Dental Pulp><Dentin><Dextrose><Disease><Disorder><ECM><ER stress><Endocrine Gland Secretion><Endoplasmic Reticulum><Endothelial Cells><Endothelium><Ergastoplasm><Event><Exposure to><Extracellular Matrix><F8VWF><FGF-2><FGF2><FGF2 gene><FGFB><FN1><Fibroblast Growth Factor 2><Fibroblast Growth Factor 2 Gene><Fibronectin 1><Fibronectins><Fracture Healing><GRP78><GRP78 gene><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Generalized Growth><Genetic Materials><Genetic Transcription><Genomics><Glucose><Glucose-Regulated Protein, 78-kD><Goals><Growth><HBGF-2><HSPA5><Harvest><Heat-Shock 70-kD Protein 5><Heparin-Binding Growth Factor 2><Heparin-Binding Growth Factor Class II><Histology><Hormones><Hydroxyapatites><Immune><Immunes><Immunoblotting><Implant><In vivo analysis><Inflammatory><Integral Membrane Protein><Intracellular Communication and Signaling><Intrinsic Membrane Protein><KO mice><Knock-out Mice><Knockout Mice><LETS Proteins><Large External Transformation-Sensitive Protein><MMPs><Matrix Metalloproteinases><Mediating><Metabolic><Mice><Mice Mammals><Minerals><Modeling><Molecular Interaction><Murine><Mus><N-terminal><NH2-terminal><Natural regeneration><Nuclear><Nucleus><Null Mouse><Nutrient><O element><O2 element><Odontoblasts><Opsonic Glycoprotein><Opsonic alpha(2)SB Glycoprotein><Osteoblasts><Outcome><Oxygen><PDGF><PECAM1><PECAM1 gene><Paracrine Communication><Paracrine Signaling><Phase><Phenotype><Platelet-Derived Growth Factor><Progenitor Cells><Prostate Epithelial Cell Growth Factor><Protein Array><Proteins><Proteomics><RNA Expression><RNA Seq><RNA sequencing><RNAseq><Regeneration><Regenerative Medicine><Regulation><Regulatory Protein><Role><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Signaling Molecule><Slice><Subcellular Process><Testing><Therapeutic><Therapeutic Effect><Therapeutic Hormone><Three-Dimensional Imaging><Time><Tissue Engineering><Tissue Growth><Tissues><Tooth><Tooth structure><Transcription><Transcription Activation><Transcription Factor Proto-Oncogene><Transcription Regulation><Transcription factor genes><Transcriptional Activation><Transcriptional Control><Transcriptional Regulation><Transgenic Mice><Transmembrane Protein><Transmembrane Protein Gene><VE-Cadherin><VEGF><VEGFA><VEGFA gene><VEGFs><VWF gene><Validation><Vascular Endothelial Cadherin><Vascular Endothelial Cadherin 1><Vascular Endothelial Growth Factor A><Vascular Endothelial Growth Factors><Vascular System><Vascularization><Vasculogenic><Vasculotropin><Waste Products><Western Blotting><Western Immunoblotting><adult progenitor><adult stem cell><alpha 2-Surface Binding Glycoprotein><angiogenesis><arm><bFGF><bioengineered tissue><biological signal transduction><bone><bone fracture healing><bone fracture repair><cadherin 5><cell stress><coping><dentin matrix protein 1><develop therapy><dmp1><endoplasmic reticulum stress><engineered exosomes><engineered tissue><exosome><extracellular><fracture repair><genetic regulatory protein><healing><immunoglobulin heavy chain-binding protein><in vivo><in vivo evaluation><in vivo testing><intervention development><migration><mineralization><mouse model><murine model><neovascularization><novel><ontogeny><overexpress><overexpression><paracrine><precursor cell><progenitor><promoter><promotor><protein blotting><pulp><regenerate><regenerate new tissue><regenerate tissue><regenerating damaged tissue><regenerating tissue><regeneration model><regenerative><regenerative model><regulatory gene product><repair><repaired><response><response biomarker><response markers><scaffold><scaffolding><sensor><social role><somatic progenitor><somatic stem cell><stem cells><subcutaneous><subdermal><teeth><therapy development><three dimensional><tissue regeneration><tissue regrowth><tissue renewal><tissue repair><tissue specific regeneration><transcription factor><transcriptome sequencing><transcriptomic sequencing><treatment development><vWF><validations><vascular><vasculogenesis>