Therapeutic S1P Drug Targets for Cranial Bone Repair

项目摘要 鞘氨醇1-磷酸(S1P)是一种多效性的自分泌和旁分泌信号小分子， 通过高亲和力G蛋白偶联受体家族引导广泛的生物反应 (S1P1-S1P5)。建议的研究将询问S1P1和S1P3亚型的协同功能 激活微血管系统，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，持续性单核细胞聚集可以 慢性炎症及阻碍成骨祖细胞募集和分化的研究进展 是组织再生所必需的。初步研究表明，S1P1通过以下途径对抗病理性炎症 防止单核细胞与激活的内皮细胞黏附，并持续递送选择性受体 靶向S1P1和S1P3亚型的三维生物降解聚合物药物促进微血管网络 在临界大小的颅骨缺损处，骨组织成熟并增加骨组织内长。因此，最重要的是 这一提议的假设是，针对S1P1和S1P3的药物激动剂的持续递送 可生物降解聚合物通过局部抑制单核细胞聚集促进骨缺损愈合 组织植入和促进间充质祖细胞(MPC)的募集以再生骨。目标 1将检验S1P1和S1P3协同作用促进间充质干细胞黏附的假设 血管内皮细胞。目的2验证S1P1/S1P3从合成的可降解物质中选择性刺激的假设 聚合物阻止单核细胞的局部聚集并促进间充质祖细胞在体内的归巢 慢性炎症的皮肤模型。AIM 3验证了S1P1和S1P3调制的假设 炎性和间充质祖细胞募集将增强骨愈合效果。

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.