Targeted delivery of nanomedicines to the coronary microvasculature during ex vivo normothermic perfusion of marginal human hearts

项目摘要/摘要 该提案详细介绍了John Stendahl博士指导的临床科学家研究和培训计划 职业发展奖。Stendahl博士的研究重点是可用于治疗的供体心脏短缺 移植。他建议通过利用体外常温机器灌流来解决这个问题 移植前设置作为评估边缘供者心脏并对其进行血管靶向治疗的平台 纳米医学。这项工作是基于这样一个假设，即实现临床上有意义的分娩 体外供者心脏的纳米药物需要：a)在损伤后恢复微血管灌流 冷缺血，以及b)纳米颗粒靶向的稳健方法。该提案的第一个目标是优化 体外常温机械灌流心脏中的微血管血流。要完成的计划 这包括用显微镜和多模式心脏成像评估微血管系统，以及 应用药物治疗恢复血流。第二个目标是设计针对血管的基因工程 在体外常温机器灌流过程中用于输送到人体心脏的纳米颗粒。这涉及到强效 纳米颗粒靶向的新方法及诊断成像在纳米颗粒评价中的进一步应用 送货。这些目标的成功实现将提供强大的、临床适用的技术来改善 供心保存，实现边缘器官的更高效利用。 斯滕达尔博士是耶鲁大学医学院心血管医学部的讲师，最近 完成高级心血管成像方面的团契培训。他提出的研究是建立在他的 生物工程、器官移植和心脏成像方面的背景。他得到了一位杰出的 由多模式心脏成像专家阿尔伯特·辛努萨斯医学博士和格雷戈里·蒂特金组成的导师团队， 他是靶向纳米颗粒输送和器官机器灌流方面的专家。拟议的工作充分利用了 耶鲁医学院的卓越设施，包括最先进的医学成像设备。Dr。 Stendahl的科学和专业发展的结构化培训计划包括讲座、课程作业 科学和伦理，与导师和顾问的私人会议，以及出席国家会议 与心脏成像、治疗性交付和器官移植有关。他计划利用这一知识和 在指导培训期间获得的数据，以产生独立研究资金的申请。在……里面 总结，这份提案概述了斯滕达尔博士的科学研究计划，并描述了指导和 机构支持，以促进他的发展，并为他作为一名成功的职业生涯做好准备 独立调查员。

PROJECT SUMMARY/ABSTRACT This proposal details Dr. John Stendahl’s research and training plan for a Mentored Clinical Scientist Research Career Development Award. Dr. Stendahl’s research focuses on the shortage of donor hearts available for transplantation. He proposes to address this issue by utilizing ex vivo normothermic machine perfusion in the pretransplant setting as a platform to assess marginal donor hearts and treat them with vascular-targeted nanomedicines. This work is based on the hypothesis that achieving clinically significant delivery of nanomedicines in ex vivo donor hearts requires: a) restoration of microvascular perfusion following the insult of cold ischemia, and b) robust methods of nanoparticle targeting. The first aim of the proposal is to optimize microvascular blood flow in hearts undergoing ex vivo normothermic machine perfusion. The plan to accomplish this involves evaluation of the microvasculature with microscopy and multimodal cardiac imaging, and the application of pharmacologic treatments to restore flow. The second aim is to engineer vascular-targeted nanoparticles for delivery to human hearts during ex vivo normothermic machine perfusion. This involves potent new methods of nanoparticle targeting and further application of diagnostic imaging to assess nanoparticle delivery. Successful completion of these aims will provide powerful, clinically adaptable technologies to improve donor heart preservation and achieve more efficient usage of marginal organs. Dr. Stendahl is an instructor in the Yale School of Medicine’s Section of Cardiovascular Medicine and recently completed fellowship training in Advanced Cardiovascular Imaging. His proposed research builds upon his backgrounds in bioengineering, organ transplantation, and cardiac imaging. He is supported by an outstanding mentorship team consisting of Albert Sinusas, MD, an expert in multimodal cardiac imaging, and Gregory Tietjen, PhD, an expert in targeted nanoparticle delivery and machine perfusion of organs. The proposed work leverages outstanding facilities at the Yale School of Medicine, including state-of-the-art medical imaging equipment. Dr. Stendahl’s structured training plan for scientific and professional development includes lectures, coursework in science and ethics, personal meetings with mentors and consultants, and attendance at national meetings related to cardiac imaging, therapeutic delivery, and organ transplantation. He plans to utilize the knowledge and data gained during the mentored training period to generate applications for independent research funding. In summary, this proposal outlines Dr. Stendahl’s plan for scientific investigation and describes the mentoring and institutional support that is present to foster his development and prepare him for a successful career as an independent investigator.