Phospholipid Growth Factors for Therapeutic Arteriogenesis and Tissue Engineering

描述（由申请人提供）：该提案的重点是开发新策略，通过治疗性诱导动脉生成来促进成熟微血管网络的生长。动脉生成是新的小动脉形成和现有的小动脉结构扩大的过程，有效地增加了阻力微血管的数量和直径，这对手术移植或缺血性损伤后的组织保存至关重要。初步研究表明，从可生物降解的聚合物中持续递送鞘氨醇-1-磷酸（S1 P）显著增强了体内小动脉的管腔直径扩大;这是动脉生成的一个标志。S1 P是一种多效性自分泌和旁分泌信号小分子，通过高亲和力G蛋白偶联受体家族（S1 P1、S1 P2、S1 P3）调节内皮细胞（EC）和平滑肌细胞（SMC）的行为。提出的活动的动机源于令人兴奋的新进展，在合成的药理学激动剂和拮抗剂的S1 P受体。最近，我们证明，在体内传递的S1 P1的选择性药理学激动剂显着增加小动脉直径扩大和血管的维护超过S1 P本身。S1 P1诱导的动脉生成的结果表明，局部递送S1 P受体靶向药物以改善组织工程和再生医学的愈合结果的新可能性令人兴奋。为此，探索性实验现在证明，植入生物可降解的三维（3D）支架，将S1 P1选择性化合物递送到临界尺寸的颅骨骨缺损，显著增加骨组织向内生长和骨修复组织中SMC投资微血管的比例。目的1将量化局部调节SMC增殖和管腔直径扩大在微血管网络在体内通过持续释放S1 P从合成的生物可降解聚合物。目的2检验S1 P诱导的小动脉直径增大需要SMCs中S1 P1激活的假设。目的3：验证S1 P1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：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，目前估计，在美国每年仅肌肉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，开发有效的策略来血管化新的组织工程器官和组织以维持它们在体内的活力是显著的医学需求。

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.