Phospholipid Growth Factors for Therapeutic Arteriogenesis and Tissue Engineering

描述（由申请人提供）：本提案的重点是开发新的策略，通过治疗性诱导动脉生成来促进成熟微血管网络的生长。动脉发生是指新的小动脉形成，现有的小动脉在结构上扩大，有效地增加了抵抗性微血管的数量和直径，这对手术移植或缺血性损伤后组织的保存至关重要。初步研究表明，生物可降解聚合物持续递送鞘氨醇-1-磷酸（S1P）可显著增强体内小动脉的管腔直径扩大；一个是动脉形成的标志。S1P是一种多效性自分泌和旁分泌信号小分子，通过高亲和G蛋白偶联受体家族（S1P1, S1P2, S1P3）调节内皮细胞（ECs）和平滑肌细胞（SMCs）的行为。提出活动的动机源于S1P受体的药理激动剂和拮抗剂合成的令人兴奋的新进展。最近，我们证明了S1P1选择性药理激动剂的体内递送比S1P1本身显著增加小动脉直径扩大和血管维持。s1p1诱导的动脉生成的结果表明，局部递送S1P受体靶向药物以改善组织工程和再生医学的愈合效果具有令人兴奋的新可能性。为此，探索性实验表明，将具有S1P1选择性化合物的生物可降解三维（3D）支架植入临界尺寸的颅骨骨缺损，可显著增加骨组织长入和骨修复组织中smc投资微血管的比例。AIM 1将通过合成可生物降解聚合物中S1P的持续释放，量化体内微血管网络中SMC增殖和管腔直径扩大的局部调控。AIM 2验证了S1P1诱导的小动脉直径增大需要在SMCs中激活S1P1的假设。AIM 3验证了s1p1诱导的微血管重塑调节将增强骨愈合结果的假设。公共卫生相关性：对创伤、损伤或丢失的器官和组织进行功能的替换或恢复是一个日益重要的临床问题。据估计，在2002年等待器官移植的79512名患者中，只有24422人接受了器官移植。此外，据目前估计，仅在美国，每年就有超过150万例肌肉骨骼损伤需要组织移植重建，并且随着人口预期寿命的增加，这些数字将继续增长。因此，发展有效的策略，使新的组织工程器官和组织血管化，以维持其在体内的生存能力是一个重要的医学需求。

DESCRIPTION (provided by applicant): 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. 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 musculoskeletal 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 vascularize new tissue engineering organ and tissues to sustain their viability in vivo is a significant medical need.