Phospholipid Growth Factors for Therapeutic Arteriogenesis and Tissue Engineering

这项建议的重点是开发新的策略，以促进成熟的微血管的生长 通过治疗性诱导动脉生成形成网络。动脉生成是形成新的小动脉的过程。 和现有的微动脉结构扩大，有效增加阻力的数量和直径 对于外科移植或缺血损伤后组织的保存至关重要的微血管。 初步研究表明，可生物降解的鞘氨醇-1-磷酸(S1P)具有缓释作用 聚合物显著增强体内小动脉的管腔直径扩大；其中之一是 动脉形成。S1P是一种多效性自分泌和旁分泌信号小分子，调节 内皮细胞(ECs)和平滑肌细胞(SMC)通过高亲和力G蛋白家族的行为- 偶联受体(S1P1、S1P2、S1P3)。拟议活动的动机源于令人兴奋的新事物 S1P受体药理激动剂和拮抗剂的合成研究进展最近，我们 表明S1P1选择性药理激动剂的体内释放显著增加 动脉内径增大和血管维持超过S1P本身。S1P1诱导的结果 动脉形成提示局部递送S1P受体靶向药物以改善的令人兴奋的新可能性 组织工程和再生医学的治愈结果。为此，现在的探索性实验 证明植入可生物降解的三维(3D)支架可选择性地传递S1P1 化合物到临界大小的颅骨骨缺损显著增加骨组织向内生长和 SMC包被的微血管在骨修复组织中的比例。目标1将量化对SMC的地方监管 体内微血管网络的增殖和管腔内径增大通过持续释放 S1P来自合成的可生物降解聚合物。目的2验证S1P诱导的小动脉直径的假设 扩大需要激活S1P1在SMC中。目的3验证S1P1诱导的细胞外信号调节的假说 微血管重塑将增强骨愈合效果。

The focus of this proposal is to develop new strategies to promote the growth of mature microvascular networks by therapeutic induction of arteriogenesis. Arteriogenesis is the process by which new arterioles form and existing arterioles structurally enlarge, effectively increasing the number and diameter of resistance microvessels that are critical to the preservation of tissues after surgical transplantation or ischemic injury. Preliminary studies show that sustained delivery of sphingosine-1-phosphate (S1P) from biodegradable polymers significantly enhances lumenal diameter enlargement of arterioles in vivo; one is one hallmark of arteriogenesis. S1P is a pleiotropic autocrine and paracrine signaling small molecule that regulates the behavior of endothelial cells (ECs) and smooth muscle cells (SMCs) through a family of high-affinity G protein- coupled receptors (S1P1, S1P2, S1P3). The motivation for the proposed activities stems from exciting new advances in the synthesis of pharmacological agonists and antagonists of S1P receptors. Recently, we demonstrated that in vivo delivery of selective pharmacological agonists of S1P1 significantly increases arteriolar diameter enlargement and vessel maintenance over S1P itself. The results of S1P1-induced arteriogenesis suggest exciting new possibilities for locally delivering S1P receptor targeted drugs to improve healing outcomes in tissue engineering and regenerative medicine. To this end, exploratory experiments now demonstrate that implantation of biodegradable three-dimensional (3D) scaffolds delivering S1P1 selective compounds to critical size calvarial bone defects significantly increases osseous tissue ingrowth and the proportion of SMC-invested microvessels in boney repair tissues. AIM 1 will quantify local regulation of SMC proliferation and lumenal diameter enlargement in microvascular networks in vivo via the sustained release of S1P from synthetic biodegradable polymers. AIM 2 tests the hypothesis that S1P-induced arteriolar diameter enlargement requires activation of S1P1 in SMCs. AIM 3 tests the hypothesis that S1P1-induced regulation of microvessel remodeling will enhance bone healing outcomes.