Therapeutic S1P Drug Targets for Cranial Bone Repair

描述（由申请人提供）：磷酸鞘氨醇（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（S1P1-S1P5）家族指导广泛的生物反应。拟议的研究将询问S1P1和S1P3亚型激活在微血管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的关键组成部分，但持续的单核细胞积累可能发展为慢性炎症，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，S1P1通过阻止单核细胞粘附到活化的内皮来对抗病理性炎症，并且从3-D可生物降解聚合物中持续递送靶向S1P1和S1P3亚型的受体选择性药物可促进微血管网络成熟并增加临界尺寸颅骨缺损的骨组织长入。因此，该建议的总体假设是，从可生物降解聚合物中持续递送靶向S1P1和S1P3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和促进间充质祖细胞（MPCs）的招募来促进骨缺损愈合。AIM 1将检验S1P1和S1P3协同作用促进间充质干细胞粘附内皮的假设。AIM 2在慢性炎症皮肤模型中验证了合成可降解聚合物选择性刺激S1P1/S1P3可阻止单核细胞的局部积聚并促进间充质祖细胞归巢的假设。AIM 3验证了S1P1和S1P3调节炎症和间充质祖细胞募集将增强骨愈合结果的假设。

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.