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.

总结 随着我们老龄化人口的增长，国家对容易获得和可靠的小直径 用于旁路移植术（用于冠状动脉和其他小动脉）和血液透析通路的导管，作为当前选项 是有限的。虽然小直径组织工程血管移植物（TEVG）已显示出巨大的临床前景， 我们目前对它们的理解几乎完全来自于对年轻接受者的宣传， 尽管老年患者是最常需要动脉旁路或血液透析的人群。 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物抑制剂- 1（派-1），这可能会危及TEVG的成功。因此，本提案的目标是了解 我们的小直径TEVG在老年和年轻接受者中的表现如何不同，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目标，每个目标都有自己的可检验假设： 具体目标1 -评价受体年龄如何影响TEVG植入的成功率和水平 循环派-1我们假设老年受者的TEVG重塑和通畅性受损 与年轻或中年受者的移植物相比，派-1水平升高与 年龄增长。这一目标的重要结果将是确定中年或老年接受者是否 是否有能力产生成功的TEVG，以及是否增加的血浆派-1与TEVG失败相关。 具体目标2 -测试药理学派-1拮抗作用对TEVG成功的影响 植入老年动物体内。派-1通过防止过早的凝块去除而发挥关键的生理作用 然而，派-1的慢性升高与心血管疾病的发病率增加有关。 FDA批准的治疗2型糖尿病的药物二甲双胍已被证明可以抑制派-1的产生。初步 研究表明，Klotho是一种与人类寿命延长有关的蛋白质，可以降低与年龄相关的派-1 受伤的肌肉。我们假设，通过补充抗纤溶酶原激活物抑制剂， Metabolic或Klotho将使我们的TEVG的成功率（通畅率）恢复到年轻动物的成功率。 创新：尽管老年人血管疾病的发生率不成比例，但 TEVG的临床试验很少使用老年动物模型。拟议工作的创新包括： 现成的无细胞管状支架的独特组合，派-1水平和TEVG的评估 在不同年龄接受者中的表现，以及使用FDA- 批准的糖尿病药物Metabolic和长寿相关蛋白Klotho，以改善与年龄相关的缺陷 TEVG性能。这里提出的精心选择的研究组合不仅是 为最需要的人-老年患者-量身定制可翻译的TEVG，但也可能是范例- TEVG和其他基于组织工程的治疗方法在临床前测试中的转变。