Phospholipid Growth Factors for Therapeutic Arteriogenesis and Tissue Engineering

描述(申请人提供)：本提案的重点是开发新的策略，通过治疗性地诱导动脉生成来促进成熟的微血管网络的生长。动脉生成是指形成新的小动脉和扩大现有小动脉的结构，有效地增加阻力微血管的数量和直径，这些微血管对于外科移植或缺血损伤后组织的保存至关重要。初步研究表明，从可生物降解的聚合物中持续释放鞘氨醇-1-磷酸(S1P)显著增强了体内小动脉的管腔直径扩大；其中之一是动脉形成的标志之一。S1P是一种多效性自分泌和旁分泌信号小分子，通过一系列高亲和力G蛋白偶联受体(S1P1、S1P2、S1P3)调节内皮细胞(ECs)和平滑肌细胞(SMC)的行为。所提出的活动的动机源于在合成S1P受体的药理激动剂和拮抗剂方面取得的令人兴奋的新进展。最近，我们证明了选择性药物激动剂S1P1的体内释放显著增加了S1P本身的动脉内径扩大和血管维持。S1P1诱导的动脉形成的结果表明，局部输送S1P受体靶向药物以改善组织工程和再生医学的愈合结果具有令人兴奋的新可能性。为此，探索性实验现在证明，植入可生物降解的三维(3D)支架，将S1P1选择性化合物输送到临界大小的颅骨缺损处，显著增加骨组织的内长和SMC投资的微血管在骨修复组织中的比例。目的1将通过从合成的生物可降解聚合物中持续释放S1P来量化体内微血管网络中SMC增殖和管腔直径扩大的局部调节。目的2验证S1P诱导的小动脉内径增大需要S1P1在SMC激活的假说。目的3验证S1P1诱导的微血管重塑调节将促进骨愈合结果的假说。公共卫生相关性：替换或恢复受损、受损或丢失的器官和组织的功能是一个日益重要的临床问题。据估计，2002年只有24,422人接受了可能在移植等待名单上的79,512名患者的器官移植。此外，目前估计，在美国，仅肌肉骨骼损伤每年就有超过150万人需要组织移植重建，而且随着人口预期寿命的增加，这个数字还将继续增长。因此，开发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.