MK2 Inhibitory Nanoplexes to Enhance Long-Term Vascular Graft Patency

MK2 抑制性纳米复合物可增强血管移植物的长期通畅性

• 批准号: 9463239
• 负责人: Craig Lewis Duvall
• 金额: $ 5.76万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9463239
• 关键词: Adopted; Adverse effects; Aftercare; Alpha Cell; Anastomosis - action; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Autologous; Bathing; Biological Sciences; Biology; Biomedical Engineering; Blood Vessels; Bypass; CREB1 gene; Cell Proliferation; Cells; Cessation of life; Clinical Trials; Coronary Artery Bypass; Coronary heart disease; Data; Deposition; Dose; Drug Delivery Systems; Drug Kinetics; Endosomes; Engineering; Ensure; Extracellular Matrix; Failure; Family suidae; Formulation; Funding; Future; Goals; HSPB1 gene; Harvest; Heart; Heterogeneous-Nuclear Ribonucleoproteins; High Pressure Liquid Chromatography; Human; Hydrophobicity; Hyperplasia; Inflammation; Injury; Internal carotid artery structure; Intervention; Leg; Length; Libraries; Limb structure; Longevity; MAPK14 gene; MAPKAPK2 gene; Measures; Mechanics; Membrane; Methods; Mitogens; Modeling; Muscle Cells; Myocardial Infarction; Nanotechnology; Operative Surgical Procedures; Outcome; Pathogenesis; Patients; Penetration; Peptides; Performance; Peripheral; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Phenotype; Phosphorylation; Phosphotransferases; Polymer Chemistry; Polymers; Pre-Clinical Model; Process; Proliferating; Protocols documentation; Publishing; Recurrence; Safety; Sampling; Saphenous Vein; Site; Smooth Muscle; Specificity; Stenosis; Stress; Surgeon; System; Technology; Testing; Time; Tissues; Toxic effect; Translations; Transplantation; Treatment Efficacy; Vascular Graft; Vascular Smooth Muscle; Vein graft; Veins; Vesicle; Work; base; brief intervention; density; design; graft failure; healing; improved; in vivo; inhibitor/antagonist; insight; migration; multidisciplinary; nanomedicine; novel; operation; particle; physical property; prevent; public health relevance; response to injury; serum sodium transport inhibitor; treatment strategy; uptake

 DESCRIPTION (provided by applicant): Coronary artery bypass grafting (CABG) with autologous human saphenous vein (HSV) is the best available treatment for severe coronary heart disease, but long-term graft patency is problematic. The per patient vein graft failure 12-18 months after CABG was 45% in the recent PREVENT IV trial (N=1,920). Vein graft failure predisposes patients to additional operations, myocardial infarction, recurrent angina, limb loss, and death. Graft failure is primarily attributable to intimal hyperplasia (IH), the process by whic vascular smooth muscle cells (VSMCs) migrate, proliferate, and deposit extracellular matrix (ECM) into a neointima that causes stenosis. We have identified MAPKAP kinase II (MK2) as a potential target for pharmacological intervention for preventing vascular graft IH. MK2 is activated directly by p38 mitogen activated kinase (MAPK), which is triggered by the mechanical and environmental stresses on the graft during transplant. Because p38 MAPK functions are diverse, p38 inhibitors cause undesirable side effects. Thus, MK2 is a logical target for inhibitin a proximal trigger of IH, and the central hypothesis of this proposal is that sustained intracellulr pharmacological inhibition of MK2 will prevent IH and improve long-term graft patency. A "cell- penetrating" peptidic MK2 inhibitor (MK2i) developed by project collaborators has high specificity and low toxicity, but barriers against intracellular delivery hinder its efficacy. Mechanistic studies support the notion that MK2i has promising anti-inflammatory and anti-fibrotic activity, but its potency and longevity of action are limited by internalization into and sequestration within intracellular late endosomal vesicles. To overcome the endosomal barrier, a novel polymer-based MK2i "nanoplex" (MK2i-NP) design has been developed in the PI's lab that improves cell internalization and endosomal escape of the MK2i peptide. Our published data verify that formulation of MK2i into endosomolytic MK2i-NPs increases peptide intracellular delivery and produces more potent and longer-lasting bioactivity relative to treatment with the free peptide. Rapid uptake and durable intracellular retention of MK2i-NPs are key criteria for this application because a brief (30 minute) treatment of the HSV tissue at the time of explant, during the period when the surgeon is preparing the site where the anastomosis will be placed, must protect the graft throughout the post-surgery healing phase. This project seeks to optimize and better elucidate the mechanism of MK2i-NPs and then to test this therapy for efficacy in inhibiting IH pathogenesis in advanced preclinical models.

 描述（由适用提供）：具有自体性人性静脉（HSV）的冠状动脉搭桥术（CABG）是针对严重冠心病的最佳治疗方法，但长期的移植物通气是有问题的。 Per患者静脉移植失败12-18 在最近的预防IV试验中，CABG后几个月为45％（n = 1,920）。静脉移植衰竭使患者易于进行其他手术，心肌梗塞，经常性心绞痛，肢体损失和死亡。移植物失败是归因于内膜增生（IH）的主要，这是Whic血管平滑肌细胞（VSMC）的过程，迁移，增殖和沉积细胞外基质（ECM）迁移到引起狭窄的新内膜中。我们已经将MAPKAP激酶II（MK2）确定为防止血管移植IH的药物干预的潜在靶标。 MK2通过p38有丝分裂原活化激酶（MAPK）直接激活，该激酶是由移植过程中移植物上的机械和环境应力触发的。由于p38 MAPK功能是潜水员，因此p38抑制剂会导致不良的副作用。这是MK2是IH近端触发抑制素的逻辑靶标，并且该提案的核心假设是，MK2的持续性药物内药物抑制作用将防止IH并提高长期谷物专注。项目合作者开发的一种“穿透性”肽MK2抑制剂（MK2I）具有高特异性和低毒性，但针对细胞内递送的障碍阻碍了其有效性。机械研究支持MK2I具有有希望的抗炎和抗纤维化活性的观念，但是其效力和寿命的寿命受到内在化和隔离性内体内体内体内体内蔬菜的限制。为了克服内体屏障，在PI的实验室中已经开发了一种新型的聚合物MK2I“纳米旋转”（MK2I-NP）设计，可改善MK2I Pepper的细胞内在化和内体逃逸。我们已发表的数据验证了MK2I对内体元MK2I-NPS的公式增加了肽内递送，并相对于用游离肽的治疗而产生更大的潜在和持久的生物活性。 MK2I-NP的快速吸收和耐用的细胞内保留是此应用的关键标准，因为在外科医生准备将厌氧症的部位准备在外科医生准备位置的时期，在外科医生准备将放置厌氧的部位的期间进行了短暂（30分钟）的处理，必须在整个术后治疗阶段保护移植物。该项目旨在优化和更好地阐明MK2I-NP的机制，然后测试该疗法以抑制高级临床前模型中IH发病机理的效率。