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

• 批准号: 10707373
• 负责人: Anne George
• 金额: $ 50.74万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 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/10707373
• 关键词: 3-Dimensional; ATF6 gene; Adsorption; Angiogenic Factor; Angiogenic Proteins; Appearance; Binding; Biological Assay; Blood Vessels; Bone Matrix; Calcium; Cell Maintenance; Cell Nucleus; Cell Proliferation; Cell Surface Receptors; Cell Survival; Cell physiology; Cells; 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; 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; Odontoblasts; Osteoblasts; Outcome; Oxygen; 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; 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; coping; 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; 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

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，重要的是要及时出现血管。 因此，重生牙本质 - 羽毛复合物的组织工程策略需要 建立脉管系统以提供氧气，营养素，激素，免疫细胞，矿物质 还有助于清除炎症期间的细胞碎片和代谢废物 和康复的再生阶段。 DMP1（牙本质基质蛋白1）是关键调节蛋白 骨和牙本质矿化。我们首先证明了它在 调节骨和骨外属物质的羟基磷灰石成核和生长 牙本质。随后，我们证明了DMP1位于 骨细胞和前牙本质细胞，因此用作信号分子并促进 这些前体细胞的分化。最近我们发现DMP1可以刺激 释放细胞内钙在骨细胞和前细胞细胞中的释放。细胞内的耗竭 内质网的钙导致ER应激。细胞应对ER应力通过 激活“展开的蛋白质反应”（UPR）。我们最近的观察之一是DMP1 刺激可以促进VEGF和其他促血管生成因子的分泌。因此，我们 假设DMP1功能激活的ER应力以促进成人的转化 干细胞，例如牙髓干细胞到内皮细胞，从而促进 血管生成。为了确定DMP1促进的机制 血管生成，我们将检查UPR信号通路。 UPR由三个ER发起 跨膜蛋白，我们的初步数据表明DMP1刺激激活了 UPR的ATF6（激活转录因子6）。据此，我们建议 研究ATF6介导ER下VEGF转录调控的机制 压力。在牙本质修复和再生期间，一个主要挑战是维护细胞 取决于功能性血管系统的可用性。根据，我们会 测试DMP1体内浆中DMP1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疗法很有价值 骨骼或牙齿中的骨折修复以恢复丢失，损坏或患病的牙本质 - 复杂的。