Phospholipid Growth Factors for Therapeutic Arteriogenesis and Tissue Engineering

用于治疗性动脉生成和组织工程的磷脂生长因子

基本信息

批准号：
8895064
负责人：
Edward A. Botchwey
金额：
$ 27.23万
依托单位：
GEORGIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8895064
关键词：
3-Dimensional Address Affinity Agonist Animals Attenuated Autocrine Communication Behavior Biocompatible Materials Bone Regeneration Bromodeoxyuridine Caliber Calvaria Cell Proliferation Cells Cephalic Clinical Data Defect Development Dorsal Skinfold Window Chamber Model Dose Drug Targeting Encapsulated Endothelial Cells Ensure Family Figs - dietary G-Protein-Coupled Receptors Glycolates Growth Growth Factor Growth and Development function H218 Protein Half-Life Healed Immunohistochemistry Implant In Vitro Injury Investigation Investments Kinetics Knock-out Left Life Expectancy LoxP-flanked allele Maintenance Mediating Medical Microspheres Modeling Motivation Mus Operative Surgical Procedures Organ Organ Transplantation Osteogenesis Outcome Paracrine Communication Patients Pericytes Phenotype Phospholipids Population Process Radiolabeled Rattus Receptor Signaling Regenerative Medicine Regulation Relative (related person)Resistance Role Signal Transduction Smooth Muscle Myocytes Sphingosine-1-Phosphate Receptor Supporting Cell Testing Therapeutic Tissue Engineering Tissue Grafts Tissue Preservation Tissues Transplantation Vascularization Waiting Lists arteriole autocrine base biodegradable polymer bone bone healing cell motility density edg-1 Protein edg-3 Protein electric impedance gain of function healing human MYH11 protein implantation improved in vivo loss of function musculoskeletal injury offspring radiotracer reconstruction research study response restoration scaffold sensor small molecule sphingosine 1-phosphate stem tissue repair tomography

3-Dimensional Address Affinity Agonist Animals Attenuated Autocrine Communication Behavior Biocompatible Materials Bone Regeneration Bromodeoxyuridine Caliber Calvaria Cell Proliferation Cells Cephalic Clinical Data Defect Development Dorsal Skinfold Window Chamber Model Dose Drug Targeting Encapsulated Endothelial Cells Ensure Family Figs - dietary G-Protein-Coupled Receptors Glycolates Growth Growth Factor Growth and Development function H218 Protein Half-Life Healed Immunohistochemistry Implant In Vitro Injury Investigation Investments Kinetics Knock-out Left Life Expectancy LoxP-flanked allele Maintenance Mediating Medical Microspheres Modeling Motivation Mus Operative Surgical Procedures Organ Organ Transplantation Osteogenesis Outcome Paracrine Communication Patients Pericytes Phenotype Phospholipids Population Process Radiolabeled Rattus Receptor Signaling Regenerative Medicine Regulation Relative (related person)Resistance Role Signal Transduction Smooth Muscle Myocytes Sphingosine-1-Phosphate Receptor Supporting Cell Testing Therapeutic Tissue Engineering Tissue Grafts Tissue Preservation Tissues Transplantation Vascularization Waiting Lists arteriole autocrine base biodegradable polymer bone bone healing cell motility density edg-1 Protein edg-3 Protein electric impedance gain of function healing human MYH11 protein implantation improved in vivo loss of function musculoskeletal injury offspring radiotracer reconstruction research study response restoration scaffold sensor small molecule sphingosine 1-phosphate stem tissue repair tomography

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项目摘要

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.

该提案的重点是制定新的策略来促进成熟的微血管的增长通过治疗诱导动脉生成的网络。动脉生成是形成新动脉的过程现有的小动脉在结构上扩大，有效地增加了电阻的数量和直径对于手术移植或缺血性损伤后保存组织至关重要的微梗。初步研究表明，从可生物降解的聚合物显着增强了体内小动物的腔直径肿大。一个是一个标志动脉生成。 S1P是一种多效性自分泌和旁分泌信号传导小分子，可调节内皮细胞（EC）和平滑肌细胞（SMC）的行为通过高亲和力G蛋白的家族耦合受体（S1P1，S1P2，S13）。拟议活动的动机源于令人兴奋的新 S1P受体的药理学激动剂和拮抗剂的合成进展。最近，我们证明体内递送S1P1的选择性药理学激动剂会显着增加 S1P本身对小动脉直径扩大和血管维护。 S1P1诱导的结果动脉生成提出了令人兴奋的新可能性，用于局部传递S1P受体靶向药物以改进组织工程和再生医学的治愈结果。为此，现在进行探索性实验证明可生物降解的三维（3D）脚手架的植入s1p1选择性至临界大小的钙颅骨缺陷的化合物显着增加骨组织的向内生长和 Boney修复组织中SMC投资的微血管的比例。 AIM 1将量化SMC的局部调节通过持续释放的体内微血管网络中的增殖和直径扩大来自合成生物降解聚合物的S1P。 AIM 2检验了S1P诱导的小动脉直径的假设扩大需要在SMC中激活S1P1。 AIM 3检验了S1P1诱导的调节的假设微血管重塑将增强骨骼愈合结果。