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Therapeutic S1P Drug Targets for Cranial Bone Repair

颅骨修复的治疗性 S1P 药物靶点

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要鞘氨醇1-磷酸（S1 P）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蛋白偶联受体家族指导广泛的生物反应（S1P1-S1P5）。本研究将探讨S1 P1和S1 P3亚型的协同功能激活微血管系统以促进炎症消退和骨修复。虽然单核细胞募集是正常骨愈合级联反应的关键组成部分，持续的单核细胞积聚可进展为慢性炎症并阻碍成骨祖细胞的募集和分化是组织再生所必需的初步研究表明，S1 P1通过以下途径拮抗病理性炎症：阻止单核细胞粘附到活化的内皮，并且持续递送受体选择性地靶向来自三维生物可降解聚合物的S1 P1和S1 P3亚型的药物促进微血管网络成熟，并增加骨组织向内生长在临界尺寸的颅骨缺损。因此，该提案的假设是持续递送靶向S1 P1和S1 P3的药理学激动剂从生物可降解聚合物促进骨缺损愈合的局部抑制单核细胞的积累组织植入物和促进间充质祖细胞（MPC）的募集以再生骨。目的 1将检验S1 P1和S1 P3协同作用促进间充质干细胞粘附的假设到内皮。目的2：验证合成的可降解蛋白对S1 P1/S1 P3的选择性刺激，聚合物阻止单核细胞的局部积聚并促进间充质祖细胞的归巢，慢性炎症的皮肤模型。AIM 3测试了S1 P1和S1 P3调节的假设，炎症和间充质祖细胞募集将增强骨愈合结果。

项目成果

期刊论文数量（22）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Injectable tissue-engineered bone repair of a rat calvarial defect.

DOI：
10.1002/lary.20624
发表时间：
2010-05
期刊：
LARYNGOSCOPE
影响因子：
2.6
作者：
Stephan, Scott J.;Tholpady, Sunil S.;Gross, Brian;Petrie-Aronin, Caren E.;Botchway, Edward A.;Nair, Lakshmi S.;Ogle, Roy C.;Park, Stephen S.
通讯作者：
Park, Stephen S.

Delivery of bioactive lipids from composite microgel-microsphere injectable scaffolds enhances stem cell recruitment and skeletal repair.