Therapeutic S1P Drug Targets for Cranial Bone Repair

描述(申请人提供)：1-磷酸鞘氨醇(S1P)是一种多效性自分泌和旁分泌信号小脂分子，通过一系列高亲和力G蛋白偶联受体(S1P1-S1P5)引导广泛的生物反应。这项拟议的研究将询问S1P1和S1P3亚型激活在微血管系统中促进炎症消退和骨修复的协同功能。尽管单核细胞募集是正常骨愈合级联反应的重要组成部分，但持续的单核细胞聚集可发展为慢性炎症，并阻碍组织再生所需的成骨前体细胞的募集和分化。初步研究表明，S1P1通过阻止单核细胞与激活的内皮细胞黏附而拮抗病理性炎症，针对S1P1和S1P3亚型的受体选择性药物从三维生物降解聚合物中持续释放，促进微血管网络成熟，增加临界大小颅骨缺损的骨组织生长。因此，这一建议的主要假设是，从可生物降解的聚合物中持续输送针对S1P1和S1P3的药物激动剂，通过局部抑制单核细胞向组织植入物的聚集和促进间充质祖细胞(MPC)的募集来促进骨缺损的愈合。目的1验证S1P1和S1P3协同作用促进间充质干细胞与内皮细胞黏附的假说。目的2在慢性炎症皮肤模型中，验证选择性刺激合成可降解聚合物的S1P1/S1P3可防止单核细胞局部聚集并促进间充质祖细胞归巢的假说。目的3验证S1P1和S1P3调节炎性和间充质祖细胞募集将促进骨愈合的假说。 公共卫生相关性：替换或恢复受损、受损或丢失的器官和组织的功能是一个日益重要的临床问题。据估计，2002年只有24,422人接受了可能在移植等待名单上的79,512名患者的器官移植。此外，目前估计，在美国，仅骨骼损伤每年就需要进行组织移植重建，而且随着人口预期寿命的增加，这个数字还将继续增长。因此，开发有效的策略来控制炎症以促进骨组织缺损的血运重建和再生是一个重要的医学需求。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: The replacement or restoration of function to traumatized, damaged, or lost organs and tissues is an increasingly significant clinical problem. It is estimated that only 24,422 received organ transplants of a possible 79,512 patients on the transplantation wait list in 2002. In addition, it is currently estimated that over 1.5 million skeletal injuries alone will require tissue graft reconstruction in the US each year, and these numbers will continue to grow as the life expectancy of the population increases. Thus, the development of effective strategies to harness inflammation for revascularization and regeneration of osseous tissue defects is a significant medical need.