Mechanisms of Prosthetic Arterial Graft Failure

人工动脉移植失败的机制

• 批准号: 8423346
• 负责人: FRANK W LOGERFO
• 金额: $ 62.11万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-07-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8423346
• 关键词: Anastomosis - action; Animal Model; Arteries; Atherosclerosis; Bilateral; Binding; Biocompatible; Biocompatible Materials; Biology; Blood Vessels; Blood flow; Bypass; Canis familiaris; Cardiovascular Diseases; Catheters; Cell Culture Techniques; Cellular biology; Characteristics; Cholesterol; Clinical; Collaborations; Coronary Restenosis; Development; Effectiveness; Endothelial Cells; Endothelium; External Capsule; Fibroblast Growth Factor; Future; Gene Expression Alteration; Gene Silencing; Gene Targeting; Genes; Goals; Hyperplasia; Implant; In Vitro; Inflammatory; Injury; Intervention; Lead; Lesion; Link; Mediating; Microarray Analysis; Modeling; Modification; Molecular; Molecular Biology; Operating Rooms; Operative Surgical Procedures; Outcome; Pathogenesis; Pathologic Processes; Phenotype; Polymers; Positioning Attribute; Prosthesis; Pulsatile Flow; RNA Interference; Rattus; Research; Role; Site; Smooth Muscle Myocytes; Surface; System; Technology; Testing; Textiles; Therapeutic; Thrombus; Tissues; Toxic effect; Translations; Transplanted tissue; Treatment Efficacy; Ursidae Family; Vascular Endothelial Growth Factors; Vascular Graft; Veins; Work; biomaterial compatibility; biomaterial development; cadherin-11; graft failure; graft healing; heart circulation; human disease; improved; in vitro Assay; in vivo; interest; laser capture microdissection; loss of function; migration; myristoylated alanine-rich C kinase substrate; nanofiber; physical property; prevent; prototype; public health relevance; response; scaffold; thrombospondin 2; tissue repair

DESCRIPTION (provided by applicant): This is a proposal to create a biologically active prosthetic arterial graft incorporating gene silencing to an antithrombotic and pro-angiogenic surface. The research team is unique in its cohesiveness and breadth of expertise including textiles, polymers, cell biology, molecular biology, and surgery, all with an established focus on vascular grafts. This project builds on our long-standing work where we have 1) characterized the lesion of anastomotic neointimal hyperplasia (AIH) downstream of the prosthetic graft, 2) established the role of blood flow-surface interaction in AIH pathogenesis, 3) applied biologic modification to the graft surface by incorporating antithrombotic (rHirudin) and endothelial cell growth factor (VEGF) to delay thrombus formation and improve endothelialization, and 4) determined the unique gene signature associated with AIH development, including identification of high profile pathogenic targets. The goals of the current proposal are to 1) Validate the involvement of MARCKS, CDH11, and TSP2 in the pathogenesis of AIH, by means of in vitro loss-of-function studies in endothelial and smooth muscle cells using siRNA, 2) Create a bioactive electrospun nanofibrous graft material and determine optimal physical properties that it requires for effective siRNA delivery to the vasculature under pulsatile flow and operating room conditions and, 3) implant the graft prototype in a large canine animal model, after preliminary testing in a rat model, and determine sequentially its potential to deliver siRNA, effectively induce gene silencing and positively impact the development of AIH lesions, including graft healing and patency. This is a stepwise study bringing to bear a unique and appropriately broad range of expertise on the effective application of gene silencing to improve the outcome of prosthetic arterial grafts. The information will also be of interest in the larger use of materials to deliver siRNA for therapeutic purposes.

描述（由申请人提供）：这是一项创建生物活性假体动脉移植物的提案，该移植物将基因沉默结合到抗血栓和促血管生成表面。该研究团队的凝聚力和专业知识的广度是独一无二的，包括纺织、聚合物、细胞生物学、分子生物学和外科手术，所有这些都专注于血管移植。该项目建立在我们长期工作的基础上，其中我们 1) 描述了假体移植物下游吻合口新生内膜增生 (AIH) 病变的特征，2) 确定了血流-表面相互作用在 AIH 发病机制中的作用，3) 通过加入抗血栓剂 (rHirudin) 和内皮细胞生长因子 (VEGF) 来延迟血栓形成，对移植物表面进行生物修饰，并 改善内皮化，4) 确定与 AIH 发展相关的独特基因特征，包括识别重要的致病靶点。当前提案的目标是 1) 通过使用 siRNA 对内皮细胞和平滑肌细胞进行体外功能丧失研究，验证 MARCKS、CDH11 和 TSP2 在 AIH 发病机制中的参与，2) 创建生物活性电纺纳米纤维移植材料并确定在脉动流和手术室条件下将 siRNA 有效递送至脉管系统所需的最佳物理特性， 3）在大鼠模型中进行初步测试后，将移植物原型植入大型犬类动物模型中，并依次确定其传递siRNA、有效诱导基因沉默并对AIH病变发展产生积极影响的潜力，包括移植物愈合和通畅。这是一项逐步研究，在有效应用基因沉默以改善人工动脉移植效果方面提供了独特且适当广泛的专业知识。这些信息对于更广泛地使用材料来递送 siRNA 进行治疗也将很有意义。