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Role of DMP1 Mediated Paracrine Signaling in Vasculogenesis

DMP1 介导的旁分泌信号在血管生成中的作用

基本信息

批准号：
10587230
负责人：
Anne George
金额：
$ 51.32万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-20 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10587230
关键词：
3-Dimensional ATF6 gene Angiogenic Factor Angiogenic Proteins Appearance Binding Blood Vessels Bone Matrix Calcium Cell Maintenance Cell Nucleus Cell Proliferation Cell Surface Receptors Cell Survival Cell physiology Cells Cellular Assay Cellular Stress Collagen Competence Complex Complex Mixtures Confocal Microscopy Data Dental Pulp Dentin Disease Endoplasmic Reticulum Endothelial Cells Endothelium Event Exposure to Extracellular Matrix FGF2 gene Fibronectins GRP gene GRP78 gene Genetic Materials Genetic Transcription Genomics Glucose Goals Growth Harvest Histology Hormones Hydroxyapatites Immune Implant Inflammatory Integral Membrane Protein Knockout Mice Matrix Metalloproteinases Mediating Metabolic Minerals Modeling Mus N-terminal Natural regeneration Nuclear Nutrient Outcome Oxygen P-Cadherin PECAM1 gene Paracrine Communication Phase Phenotype Platelet-Derived Growth Factor Protein Array Proteins Proteomics Regenerative Medicine Regulation Role Signal Pathway Signal Transduction Signaling Molecule Slice Testing Therapeutic Therapeutic Effect Three-Dimensional Imaging Time Tissue Engineering Tissues Tooth structure Transcriptional Activation Transcriptional Regulation Transforming Growth Factor beta Transgenic Mice VEGFA gene VWF gene Validation Vascular Endothelial Growth Factors Vascular System Vascularization Waste Products Western Blotting adult stem cell angiogenesis arm bone bone fracture repair cadherin 5 dentin matrix protein 1 endoplasmic reticulum stress engineered exosomes exosome extracellular genetic regulatory protein healing in vivo in vivo evaluation migration mineralization mouse model neovascularization novel overexpression paracrine preconditioning precursor cell progenitor promoter regeneration model regenerative repaired response response biomarker scaffold sensor stem cells subcutaneous therapy development tissue regeneration tissue repair transcription factor transcriptome sequencing vasculogenesis

项目摘要

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.

为了修复或再生牙本质，及时出现血管是很重要的。