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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

基本信息

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
项目类别：
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

项目摘要

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.