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.

对于牙本质修复或再生，血管的及时出现非常重要。因此，再生牙本质-牙髓复合物的组织工程策略需要建立输送氧气、营养物质、激素、免疫细胞、矿物质的脉管系统还有助于清除炎症期间的细胞碎片和代谢废物 DMP1（牙本质基质蛋白1）是愈合和再生阶段的关键调节蛋白。我们首先证明它在骨骼和牙本质矿化中具有调节作用。骨和细胞外基质中羟基磷灰石成核和生长的调节随后，我们证明DMP1定位于牙本质细胞核。前成骨细胞和前成牙本质细胞，因此充当信号分子并促进最近我们发现DMP1可以刺激这些前体细胞的分化。前成骨细胞和前成牙本质细胞释放细胞内钙。内质网中的钙会导致内质网应激细胞通过以下方式应对内质网应激。我们最近的观察结果之一是 DMP1。刺激可以促进VEGF和其他促血管生成因子的分泌。发现 DMP1 激活的 ER 应激可促进成人转化干细胞如牙髓干细胞转化为内皮细胞，从而促进为了确定 DMP1 促进血管发生的机制。在血管发生过程中，我们将检查 UPR 信号通路 UPR 是由三个 ER 启动的。跨膜蛋白，其中我们的初步数据表明 DMP1 刺激 UPR 的 ATF6（激活转录因子 6）臂因此，我们在此建议：研究ER下ATF6介导VEGF转录调控的机制在牙本质修复和再生过程中，一个主要挑战是细胞的维持。生存能力取决于功能性血管系统的可用性。测试 DMP1 在体内牙髓中的体内血管生成能力和治疗潜力再生模型。了解 DMP1 的复杂功能对于开发治疗方法可能很有价值修复骨骼或牙齿中的骨折，以恢复丢失、损坏或患病的牙本质牙髓复杂的。