Therapeutic S1P Drug Targets for Cranial Bone Repair

描述（由申请人提供）：鞘氨醇1-磷酸（S1 P）是一种多效性自分泌和旁分泌信号传导小脂质分子，通过高亲和力G蛋白偶联受体家族（S1 P1-S1 P5）指导广泛的生物反应。拟议的研究将探讨S1 P1和S1 P3亚型激活在微血管中的协同作用，以促进炎症消退和骨修复。尽管单核细胞募集是正常骨愈合级联的关键组成部分，但持续的单核细胞积聚可进展为慢性炎症并阻碍组织再生所需的成骨祖细胞的募集和分化。初步研究表明，S1 P1通过阻止单核细胞粘附到活化的内皮细胞来拮抗病理性炎症，并且从3-D生物可降解聚合物中持续递送靶向S1 P1和S1 P3亚型的受体选择性药物促进微血管网络成熟并增加临界尺寸颅骨缺损中的骨组织向内生长。因此，该提议的首要假设是，从生物可降解聚合物持续递送靶向S1 P1和S1 P3的药理学激动剂通过局部抑制单核细胞积聚到组织植入物并促进间充质祖细胞（MPC）的募集以再生骨来促进骨缺损愈合。目的1验证S1 P1和S1 P3协同促进间充质干细胞与内皮细胞粘附的假说。目的2检验在慢性炎症的皮肤模型中从合成的可降解聚合物选择性刺激S1 P1/S1 P3防止单核细胞的局部积聚并促进间充质祖细胞归巢的假设。目的3测试的假设，S1 P1和S1 P3的炎症和间充质祖细胞募集的调节将增强骨愈合的结果。 公共卫生相关性：创伤、受损或丧失的器官和组织的功能的替换或恢复是日益重要的临床问题。据估计，在2002年等待移植的79 512名病人中，只有24 422人接受了器官移植。此外，据目前估计，在美国每年仅骨骼损伤就需要组织移植重建超过150万例，并且随着人口预期寿命的增加，这些数字将继续增长。因此，开发有效的策略来利用炎症进行骨组织缺损的血运重建和再生是重要的医学需求。

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.