The Role of Fibrinolysis in Tissue Engineered Vascular Grafts for Aged Individuals

纤溶在老年人组织工程血管移植中的作用

• 批准号: 9979086
• 负责人: David Alan Vorp
• 金额: $ 18.08万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9979086
• 关键词: Abdomen; Acute; Address; Adipose tissue; Affect; Age; Aging; Alteplase; American; Animal Model; Animals; Arteries; Blood; Blood Circulation; Blood Vessels; Blood flow; Bypass; Caliber; Cardiovascular Diseases; Cell Proliferation; Cells; Cessation of life; Chronic; Clinical; Coagulation Process; Collagen; Coronary; Cytoskeleton; Devices; Diabetes Mellitus; Drug Metabolic Detoxication; Elastin; Elderly; End stage renal failure; Endothelial Cells; Engineering; Evaluation; Excision; Extracellular Matrix; FDA approved; Failure; Fibrin; Fibrinolysis; Foundations; Goals; Health system; Hemodialysis; Histologic; Homeostasis; Human; Hyperplasia; Implant; Incidence; Individual; Injury; Intervention; Life; Longevity; Lower Extremity; Mesenchymal Stem Cells; Metformin; Muscle; Natural regeneration; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Patients; Performance; Pharmaceutical Preparations; Pharmacology; Phenotype; Physiological; Plasma; Plasma Proteins; Plasmin; Plasminogen Activator Inhibitor 1; Play; Preclinical Testing; Production; Rattus; Role; Savings; Serum; Silk; Smooth Muscle Myocytes; Supplementation; Testing; Thrombosis; Tissue Engineering; Tubular formation; Urokinase; Vascular Diseases; Vascular Graft; Work; age related; aged; aging population; base; cohort; elastomeric; graft failure; implantation; improved; in vivo evaluation; inhibitor/antagonist; injured; innovation; juvenile animal; klotho protein; link protein; macrophage; middle age; older patient; pre-clinical; premature; preservation; prevent; response; scaffold; success; thrombogenesis; vascular tissue engineering

SUMMARY As our aging population grows, so does the national need for a readily available and dependable small-diameter conduit for bypass grafting (for coronary and other small arteries) and for hemodialysis access, as current options are limited. While small-diameter tissue engineered vascular grafts (TEVGs) have shown great clinical promise, our current understanding of them has been almost exclusively derived from implantations into young recipients, even though older patients are the demographic most commonly in need of arterial bypass or hemodialysis. Further, these older patients also typically have high levels of the plasma protein plasminogen activator inhibitor- 1 (PAI-1), which could jeopardize the success of a TEVG. Therefore, the goals of this proposal are to understand how our small diameter TEVG performs differently in aged vs young recipients and to identify an intervention that will improve performance in aged individuals. The proposed work has two Specific Aims, each with their own testable hypothesis: Specific Aim 1 – Evaluate how recipient age affects the success of TEVG implantation and levels of circulating PAI-1. We hypothesize that TEVG remodeling and patency are compromised in elderly recipients in comparison to grafts in young or middle-aged recipients, and that elevated PAI-1 levels will be associated with increasing age. The important outcome of this aim will be determining whether middle-aged or elderly recipients are competent for generating a successful TEVG, and if increased plasma PAI-1 is associated with TEVG failure. Specific Aim 2 – Test the effect of pharmacological PAI-1 antagonism on the success of TEVG implantation in aged animals. PAI-1 plays a critical physiological role by preventing premature clot removal after injury, yet chronic elevation of PAI-1 is associated with increased incidence of cardiovascular disease. Metformin, an FDA-approved drug for type 2 diabetes, has been shown to inhibit PAI-1 production. In preliminary work, we show that Klotho, a protein linked to human lifespan extension, can lower age-associated PAI-1 elevation in injured muscle. We hypothesize that antagonism of PAI-1 in aged animals by supplementation with Metformin or Klotho will restore the success (patency rate) of our TEVGs to that of younger animals. Innovation: Despite the disproportionate occurrence of vascular disease in elderly individuals, pre- clinical testing of TEVGs rarely uses aged animal models. The innovation of the proposed work includes the unique combination of an off-the-shelf cell-free tubular scaffold, assessment of PAI-1 levels and TEVG performance in different aged recipients, and evaluation of a pharmacological intervention using the FDA- approved diabetes drug Metformin and longevity-associated protein Klotho to improve age-associated deficient TEVG performance. The carefully-chosen combination of studies proposed here will not only be foundational for tailoring a translatable TEVG for those who are most in need – elderly patients – but may also be paradigm- shifting in how TEVGs and other tissue engineering-based therapies are tested preclinically.

概括 随着人口老龄化的增长，民族对随时可用且可靠的小直径的需求也是如此 旁路移植的导管（用于冠状动脉和其他小动脉）和血液透析通道，作为当前的选择 有限。小直径组织工程的血管移植物（TEVG）表现出巨大的临床承诺，但 我们目前对它们的理解几乎是从植入到年轻接受者中的， 即使老年患者是最常见的人群，需要动脉旁路或血液透析。 此外，这些老年患者通常还具有高水平的血浆蛋白纤溶酶原激活剂抑制剂 - 1（pai-1），这可能会危及tevg的成功。因此，该提议的目标是了解 我们的小直径TEVG在老年人与年轻接受者中的表现不同并确定干预措施 这将改善老年人的表现。 拟议的工作有两个具体的目标，每个目标都有自己的可检验假设： 特定目标1 - 评估受体年龄如何影响TEVG植入和水平的成功 循环pai-1。我们假设TEVG的重塑和通畅在古老的接收者中受到了损害 与年轻或中年接受者的移植物相比，PAI-1水平升高将与 年龄增加。此目标的重要结果是确定中年还是年长的接受者 有能力产生成功的TEVG，如果增加等离子体PAI-1与TEVG失败有关。 具体目标2 - 测试药物PAI-1拮抗作用对TEVG成功的影响 植入老年动物。 PAI-1通过防止过早的克隆去除来发挥关键的生理作用 受伤后，PAI-1的慢性升高与心血管疾病的发生率增加有关。 二甲双胍是一种用于2型糖尿病的FDA批准药物，已显示可抑制PAI-1的产生。在初步 工作，我们表明克洛托是一种与人类寿命延伸相关的蛋白质，可以降低与年龄相关的PAI-1 受伤的肌肉高程。我们假设Pai-1在老年动物中的拮抗作用是通过补充 二甲双胍或克洛托将恢复我们的TEVG的成功（通畅率）。 创新：尽管老个人的血管疾病不成比例，但 TEVG的临床测试很少使用老化的动物模型。拟议工作的创新包括 无搁置的无细胞管状支架的独特组合，PAI-1水平和TEVG的评估 在不同老年接受者中的表现，并使用FDA-评估药物干预措施 批准的糖尿病药物二甲双胍和长寿相关蛋白klotho可改善与年龄相关的默认 TEVG性能。这里提出的研究的精心选择的组合不仅将是基础 为最需要的人（老年患者）量身定制可翻译的TEVG，但也可能是范式 - 临床上测试了TEVG和其他基于组织工程的疗法的转变。