Precision nanomedicine targeting novel endothelial mechano-sensing mechanisms

针对新型内皮机械传感机制的精密纳米医学

基本信息

批准号：
10354607
负责人：
Yun Fang
金额：
$ 80.52万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2029-05-31
项目状态：
未结题

项目摘要

PROJECT SUMMARY Endothelial mechano-transduction mechanisms are instrumental to vascular health and disease but targeting disease-causing mechano-sensing pathways remains extremely challenging. For instance, atherosclerosis preferentially develops at arterial curvatures and bifurcations where disturbed blood flow activates endothelium; however, current atherosclerosis therapies mainly target systematic risk factors but not the vasculature per se. This underscores the significance and unique opportunity to identify and target novel mechanosensitive mechanisms in activated endothelium subjected to disturbed flow. This proposal aims to first delineate novel endothelial mechano-sensing mechanisms and moreover, devise innovative precision nanomedicine approaches targeting these disease-causing mechano-sensitive pathways. This R35 mechanism will provide us a unique opportunity to synergistically combine our efforts in endothelial biology (R01 HL136765) and vascular nanomedicine (R01 HL138223), testing paradigm shift hypotheses related to endothelial mechanotransduction and addressing an unmet medical need in vascular therapies. Specifically, seminal work from us and colleagues along with our unpublished data identified three new layers of molecular controls of endothelial mechano-transduction: epi-genome (DNA chemical modification), epi-transcriptome (mRNA chemical modifications) and metabolism (glycolysis and oxidative phosphorylation). The overall goals of this project are to 1) identify novel regulators governing the endothelial epi-genomic, epi-transcriptomic, and metabolic responses to blood flow and 2) engineer innovative nanoparticles which target each of these pathways treating vascular complications in vivo. The scientific premise is that innovative nanoparticles can effectively deliver therapeutic nucleotides targeting these mechano-sensitive pathways in activated endothelium. This proposal addresses a significant knowledge gap in endothelial biology and an uncharted territory in vascular medicine, research directions being pursued by only a small number of laboratories world-wide. Our team has laid much the groundwork in developing multidisciplinary knowledge, technologies, and animal models necessary to investigate new endothelial mechanotransduction paradigms and moreover, devise precision nanomedicine strategies for future tailor-made vascular therapies. Successful completion of the proposal will establish a proof of concept of targeted nanomedicine in vascular wall-based therapies. The proposed studies should further preclinical development and eventual clinical testing of new therapeutic strategies to treat vascular diseases.

项目摘要内皮机械转移机制对血管健康和疾病起着重要作用，但靶向引起疾病的机械感应途径仍然极具挑战性。例如，动脉粥样硬化优先在动脉曲率和分叉上发展，而流动受到干扰激活内皮；但是，目前的动脉粥样硬化疗法主要针对系统的危险因素，但不是针对系统的危险因素脉管系统本身。这强调了识别和针对新颖的重要性和独特的机会激活的内皮中的机械敏感机制受到干扰的流动。该建议旨在首先描述新颖的内皮机械感应机制和设计创新精度纳米医学方法针对这些引起疾病的机械敏感途径。这种R35机制将为我们提供一个独特的机会，可以协同结合我们的努力内皮生物学（R01 HL136765）和血管纳米医学（R01 HL138223），测试范式移位与内皮机械转导的假设和血管中未满足的医疗需求有关的假设疗法。具体而言，来自我们和同事的开创性工作以及我们未发表的数据确定了三个内皮机械转基的分子控制的新层：Epi-genome（DNA化学修饰），表观转录组（mRNA化学修饰）和代谢（糖酵解和氧化磷酸化）。该项目的总体目标是1）确定有关内皮的新型监管机构 Epi-Genomic，Epi-Transcrentomic和对血流的代谢反应和2）工程师创新靶向这些途径的纳米颗粒在体内治疗血管并发症。科学前提是创新的纳米颗粒可以有效地提供针对这些的治疗核苷酸激活的内皮中的机械敏感途径。该提案解决了内皮生物学和未知领域的显着知识差距在血管医学中，全球少数实验室仅追求研究方向。我们的团队为发展多学科知识，技术和动物奠定了基础研究新的内皮机械转导范式的必要模型和设计精密纳米医学策略，用于未来量身定制的血管疗法。成功完成提案将在基于血管壁的疗法中建立靶向纳米医学的概念证明。这拟议的研究应进一步进行临床前开发和最终的临床测试治疗血管疾病的策略。