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: 10630052
• 负责人: Yun Fang
• 金额: $ 81.1万
• 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/10630052
• 关键词: Address; Animal Model; Atherosclerosis; Biology; Blood Vessels; Blood flow; Cause of Death; Chemicals; DNA; Data; Disease; Endothelium; Engineering; Future; 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; epigenome; epigenomics; epitranscriptome; epitranscriptomics; in vivo; innovation; mechanotransduction; multidisciplinary; nanomedicine; nanoparticle; novel; novel therapeutic intervention; preclinical development; research clinical testing; response

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 Specifically, seminal work from us and colleagues along with our unpublished data identified three new layers of molecular controls of endothelial mechano-transduction: epi-genome (DNA chemical modification), epi-transcriptome (mRNA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

项目概要 内皮机械传导机制有助于血管健康和疾病，但 针对致病的机械传感途径仍然极具挑战性。例如， 动脉粥样硬化优先发生在血流受到干扰的动脉曲率和分叉处 激活内皮细胞；然而，目前的动脉粥样硬化治疗主要针对系统性危险因素，而不是针对 脉管系统本身。这强调了识别和瞄准小说的重要性和独特的机会 活化内皮细胞中受到血流扰动的机械敏感机制。该提案旨在首先 描绘新颖的内皮机械传感机制，并设计创新的精度 针对这些引起疾病的机械敏感途径的纳米医学方法。 R35 机制将为我们提供一个独特的机会，将我们的努力协同起来， 内皮生物学（R01 HL136765）和血管纳米医学（R01 HL138223），测试范式转变 与内皮机械传导相关的假设并解决血管中未满足的医疗需求 疗法。具体来说，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 内皮机械传导分子控制的新层：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 磷酸化）。该项目的总体目标是 1）确定控制内皮细胞的新调节因子 对血流的表观基因组、表观转录组和代谢反应以及 2) 工程创新 纳米颗粒针对这些途径中的每一个治疗体内血管并发症。科学的 前提是创新的纳米颗粒可以有效地递送针对这些的治疗性核苷酸 活化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重大知识差距 在血管医学领域，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范式所必需的模型，此外，设计 未来定制血管治疗的精密纳米医学策略。圆满完成了 该提案将建立基于血管壁的靶向纳米医学疗法的概念验证。这 拟议的研究应进一步促进新疗法的临床前开发和最终临床测试 治疗血管疾病的策略。

项目成果

JAG1-NOTCH4 mechanosensing drives atherosclerosis.

JAG1-NOTCH4机械感应驱动动脉粥样硬化。

• DOI: 10.1126/sciadv.abo7958
• 发表时间: 2022-09-02
• 期刊: Science advances
• 影响因子: 13.6

Integrated systems biology approach identifies gene targets for endothelial dysfunction.

• DOI: 10.15252/msb.202211462
• 发表时间: 2023-12-06
• 期刊: MOLECULAR SYSTEMS BIOLOGY
• 影响因子: 9.9
• 作者: Pinheiro-de-Sousa, Iguaracy;Fonseca-Alaniz, Miriam Helena;Giudice, Girolamo;Valadao, Iuri Cordeiro;Modestia, Silvestre Massimo;Mattioli, Sarah Viana;Rosa Junior, Ricardo;Zalmas, Lykourgos-Panagiotis;Fang, Yun;Petsalaki, Evangelia;Krieger, Jose Eduardo
• 通讯作者: Krieger, Jose Eduardo