Therapeutic S1P Drug Targets for Cranial Bone Repair

颅骨修复的治疗性 S1P 药物靶点

• 批准号: 8543695
• 负责人: Edward A. Botchwey
• 金额: $ 33.97万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-05 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8543695
• 关键词: 3-Dimensional; Adhesions; Affinity; Agonist; Animals; Attenuated; Autocrine Communication; Biocompatible Materials; Biological; Biological Assay; Blood Circulation; Blood Vessels; Bone Growth; Bone Regeneration; Calvaria; Cell Adhesion; Cell Communication; Cells; Cephalic; Chimera organism; Chronic; Clinical; Cutaneous; Data; Defect; Development; Dorsal; Dorsal Skinfold Window Chamber Model; Dose; Drug Delivery Systems; Drug Targeting; Encapsulated; Endothelial Cells; Endothelium; Family; Figs - dietary; G-Protein-Coupled Receptors; Glycolates; Growth; Harvest; Healed; Homing; Immunohistochemistry; Implant; In Vitro; Inflammation; Inflammatory; Injection of therapeutic agent; Kinetics; Label; Left; Leukocytes; Life Expectancy; Lipids; Marrow; Measures; Medical; Mesenchymal Stem Cells; Methods; Microspheres; Modeling; Mus; Natural regeneration; Oral; Organ; Organ Transplantation; Osteoblasts; Osteoclasts; Osteogenesis; Osteoid; Outcome; Paracrine Communication; Pathologic; Patients; Pericytes; Pharmaceutical Preparations; Population; Rattus; Receptor Signaling; Recombinants; Regulation; Relative (related person); Resolution; Role; Signal Transduction; Site; Smooth Muscle Myocytes; Stem cells; Supporting Cell; TNF gene; Tail; Testing; Therapeutic; Tissue Engineering; Tissue Grafts; Tissues; Transplantation; Veins; Waiting Lists; angiogenesis; base; biodegradable polymer; bone; bone cell; bone healing; clinical application; craniofacial; cytokine; density; edg-3 Protein; gain of function; healing; implantation; in vivo; inflammatory modulation; inorganic phosphate; loss of function; migration; monocyte; osteoblast differentiation; osteoprogenitor cell; prevent; progenitor; receptor; reconstruction; research study; response; restoration; scaffold; skeletal injury; tissue regeneration; tissue repair; tomography; 3-Dimensional; Adhesions; Affinity; Agonist; Animals; Attenuated; Autocrine Communication; Biocompatible Materials; Biological; Biological Assay; Blood Circulation; Blood Vessels; Bone Growth; Bone Regeneration; Calvaria; Cell Adhesion; Cell Communication; Cells; Cephalic; Chimera organism; Chronic; Clinical; Cutaneous; Data; Defect; Development; Dorsal; Dorsal Skinfold Window Chamber Model; Dose; Drug Delivery Systems; Drug Targeting; Encapsulated; Endothelial Cells; Endothelium; Family; Figs - dietary; G-Protein-Coupled Receptors; Glycolates; Growth; Harvest; Healed; Homing; Immunohistochemistry; Implant; In Vitro; Inflammation; Inflammatory; Injection of therapeutic agent; Kinetics; Label; Left; Leukocytes; Life Expectancy; Lipids; Marrow; Measures; Medical; Mesenchymal Stem Cells; Methods; Microspheres; Modeling; Mus; Natural regeneration; Oral; Organ; Organ Transplantation; Osteoblasts; Osteoclasts; Osteogenesis; Osteoid; Outcome; Paracrine Communication; Pathologic; Patients; Pericytes; Pharmaceutical Preparations; Population; Rattus; Receptor Signaling; Recombinants; Regulation; Relative (related person); Resolution; Role; Signal Transduction; Site; Smooth Muscle Myocytes; Stem cells; Supporting Cell; TNF gene; Tail; Testing; Therapeutic; Tissue Engineering; Tissue Grafts; Tissues; Transplantation; Veins; Waiting Lists; angiogenesis; base; biodegradable polymer; bone; bone cell; bone healing; clinical application; craniofacial; cytokine; density; edg-3 Protein; gain of function; healing; implantation; in vivo; inflammatory modulation; inorganic phosphate; loss of function; migration; monocyte; osteoblast differentiation; osteoprogenitor cell; prevent; progenitor; receptor; reconstruction; research study; response; restoration; scaffold; skeletal injury; tissue regeneration; tissue repair; tomography

Project Summary Sphingosine1-phosphate (S1P) is a pleiotropic autocrine and paracrine signaling small lipid molecule that directs a wide range of biological responses through a family of high-affinity G protein-coupled receptors (S1P1-S1P5). The proposed studies will interrogate the cooperative functions of S1P1 and S1P3 subtype activation in the microvasculature to promote inflammation resolution and bone repair. Although monocyte recruitment is a critical component of the normal bone healing cascade, persistent monocyte accumulation can progress into chronic inflammation and impede recruitment and differentiation of osteoblastic progenitor cells required for tissue regeneration. Preliminary studies show that S1P1 antagonizes pathologic inflammation by preventing monocyte adhesion to activated endothelium, and that sustained delivery of receptor selective drugs targeting S1P1 and S1P3 subtypes from 3-D biodegradable polymers promotes microvascular network maturation and increases osseous tissue ingrowth in critical sized cranial bone defects. Thus, the overarching hypothesis of this proposal is that sustained delivery of pharmacological agonists targeting S1P1 and S1P3 from biodegradable polymers promotes osseous defect healing by locally suppressing monocyte accumulation to tissue implants and promoting recruitment of mesenchymal progenitor cells (MPCs) to regenerate bone. AIM 1 will test the hypothesis that S1P1 and S1P3 act synergistically to promote mesenchymal stem cell adhesion to endothelium. AIM 2 tests the hypothesis that selective stimulation of S1P1/S1P3 from synthetic degradable polymers prevents local accumulation of monocytes and promotes homing of mesenchymal progenitor cells in a cutaneous model of chronic inflammation. AIM 3 tests the hypothesis that S1P1 and S1P3 modulation of inflammatory and mesenchymal progenitor cell recruitment will enhance bone healing outcomes.

项目摘要 鞘氨酸1-磷酸盐（S1P）是一种多效性自分泌和旁分泌信号，小脂质分子 通过高亲和力G蛋白偶联受体的家族指导广泛的生物学反应 （S1P1-S1P5）。拟议的研究将询问S1P1和S1P3亚型的合作功能 在微脉管系统中激活以促进炎症分辨率和骨修复。虽然单核细胞 招募是正常骨骼愈合级联的关键组成部分，持续的单核细胞积累可以 发展成慢性炎症，阻碍成骨细胞祖细胞的募集和分化 组织再生所必需的。初步研究表明，S1P1通过 防止单核细胞粘附对活化的内皮，并持续递送受体选择性 来自3-D可生物降解聚合物的S1P1和S1P3亚型的药物促进微血管网络 成熟并增加临界大小颅骨缺陷中的骨组织向内生长。因此，总体 该提议的假设是，针对S1P1和S13的药理学激动剂的持续递送 来自可生物降解的聚合物通过局部抑制单核细胞积累来促进骨缺陷愈合 进行组织植入物并促进间充质祖细胞（MPC）的募集以再生骨骼。目的 1将测试S1P1和S13协同作用以促进间充质干细胞粘附的假设 到内皮。 AIM 2检验了一个假设，即合成降解的S1P1/S13的选择性刺激 聚合物可防止单核细胞的局部积累，并促进间充质祖细胞中的寄养 慢性炎症的皮肤模型。 AIM 3检验了S1P1和S13调制的假设 炎症和间质祖细胞募集将增强骨骼愈合结果。