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

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/10354607
• 关键词: Address; Animal Model; Atherosclerosis; Biology; Blood Vessels; Blood flow; Cause of Death; Chemicals; DNA; Data; Disease; Endothelium; Engineering; Future; Genomics; Glycolysis; Goals; Health; Knowledge; Laboratories; Medical; Medicine; Messenger RNA; Metabolic; Metabolism; Modification; Molecular; Nucleotides; Oxidative Phosphorylation; Pathway interactions; Research; Risk Factors; Seminal; Technology; Testing; Therapeutic; Vascular Diseases; Work; base; epigenome; epitranscriptome; in vivo; innovation; mechanotransduction; multidisciplinary; nanomedicine; nanoparticle; novel; novel therapeutic intervention; preclinical development; research clinical testing; response; transcriptomics

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 Specifically, seminal work from us and colleagues along with our unpublished data identified three new layers of molecular controls of endothelial mechano-transduction: epi-genome (DNA chemical modification), epi-transcriptome (mRNA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 内皮机械转导机制有助于血管健康和疾病， 靶向引起疾病的机械感测途径仍然极具挑战性。比如说， 动脉粥样硬化优先发生在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风险因素， 血管系统本身这强调了识别和瞄准新的 机械敏感性机制的激活内皮细胞受到干扰流。该提案旨在首先 描绘新的内皮机械传感机制，此外，设计创新的精度 纳米医学方法针对这些致病的机械敏感途径。 这一R35机制将为我们提供一个独特的机会，以协同方式将我们的努力联合收割机结合起来， 内皮生物学（R 01 HL 136765）和血管纳米医学（R 01 HL 138223），测试范式转换 与内皮机械转导相关的假设和解决血管中未满足的医疗需求 治疗具体来说，我们和同事的开创性工作沿着我们未发表的数据确定了三个 内皮细胞机械传导的新的分子控制层：表观基因组（DNA化学 修饰）、表观转录组（mRNA化学修饰）和代谢（糖酵解和氧化修饰） 磷酸化）。本项目的总体目标是：1）鉴定新的调控内皮细胞的调节因子， 表观基因组学、表观转录组学和对血流的代谢反应，以及2）工程创新 靶向这些通路中的每一个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目标的治疗核苷酸， 机械敏感性途径激活内皮细胞。 该提案解决了内皮生物学的重大知识缺口和未知领域 在血管医学方面，全世界只有少数实验室在从事研究方向。 我们的团队在开发多学科知识，技术和动物方面奠定了基础。 研究新的内皮机械传导模式所需的模型， 为未来量身定制的血管治疗提供精确的纳米医学策略。成功完成 该提案将建立一个基于血管壁治疗的靶向纳米医学概念的证明。的 建议的研究应进一步临床前开发和最终的临床试验， 治疗血管疾病的策略。