Precision nanomedicine targeting novel endothelial mechano-sensing mechanisms

项目总结 内皮机械转导机制有助于血管健康和疾病，但 瞄准致病的机械传感通路仍然具有极大的挑战性。例如, 动脉粥样硬化主要发生在血流紊乱的动脉弯曲处和分叉处 激活内皮；然而，目前的动脉粥样硬化治疗主要针对系统性危险因素，而不是 血管系统本身。这突显了识别和瞄准小说的重要性和独特的机会 激活型内皮细胞对扰动血流的机械敏感机制。这项提议旨在首先 描绘新的内皮机械传感机制，并设计创新的精确度 针对这些致病机械敏感途径的纳米医学方法。 这一R35机制将为我们提供一个独特的机会，协同结合我们在以下领域的努力 内皮生物学(R01 HL136765)和血管纳米医学(R01 HL138223)，测试范式转变 与血管内皮细胞机械转导相关的假说和解决血管中未满足的医学需求 治疗。具体地说，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 内皮细胞机械转导的新分子控制层次：EPI-基因组(DNA化学 表观转录组(信使核糖核酸的化学修饰)和代谢(糖酵解和氧化 磷酸化)。该项目的总体目标是：1)确定管理内皮细胞的新调节剂 EPI-基因组、表观转录和代谢对血流的反应和2)工程创新 靶向这些途径的纳米颗粒在体内治疗血管并发症。科学的 前提是创新的纳米颗粒可以有效地输送针对这些基因的治疗核苷酸 激活内皮细胞中的机械敏感通路。 这项建议解决了内皮生物学方面的重大知识差距和一个未知领域 在血管医学中，世界上只有一小部分实验室在追求研究方向。 我们的团队在开发多学科知识、技术和动物方面奠定了许多基础 研究新的内皮细胞机械转导范例所需的模型，而且，设计 为未来的血管治疗量身定做的精确纳米医学战略。圆满完成 该提案将在基于血管壁的治疗中建立靶向纳米药物的概念证明。这个 拟议的研究应进一步临床前开发和最终临床测试新的治疗方法 治疗血管疾病的策略。

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 Specifically, seminal work from us and colleagues along with our unpublished data identified three new layers of molecular controls of endothelial mechano-transduction: epi-genome (DNA chemical modification), epi-transcriptome (mRNA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.