Therapeutic nanoscale matrimeres

治疗性纳米级基质

• 批准号: 10650665
• 负责人: Jae-Won Shin
• 金额: $ 44.77万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10650665
• 关键词: Address; Adherens Junction; Affinity; Agonist; Autophagocytosis; Autophagosome; Biocompatible Materials; Biodistribution; Biogenesis; Bioinformatics; Biology; Blood Vessels; Cell Communication; Cell secretion; Cells; Cellular biology; Chemicals; Chromatin; Complex; DNA; Data; Deoxyribonuclease I; Development; Disease; Edema; Elastic Tissue; Elasticity; Endothelial Cells; Endothelium; Endotoxemia; Engineering; Environment; Extracellular Matrix; Extracellular Matrix Proteins; Extravasation; Failure; Fibronectins; Fibrosis; Genetic; Genomic DNA; Goals; Guanine + Cytosine Composition; Histones; Hydrogels; Image; Inflammatory; Injury; Integrins; Length; Lipopolysaccharides; Lung; Lysosomes; Mediating; Mediator; Molecular Biology; Molecular Conformation; Monomeric GTP-Binding Proteins; Mus; Nanostructures; Nanotechnology; Natural regeneration; Organ; Outcome; PTK2 gene; Paracrine Communication; Pathway interactions; Permeability; Physiological; Play; Process; Production; Property; Proteins; RGD (sequence); Recycling; Research Personnel; Reverse engineering; Role; Route; Signal Pathway; Signal Transduction; Sonication; Structure of parenchyma of lung; Testing; Therapeutic; Tissues; Trauma; Vascular Permeabilities; Vascularization; Work; cadherin 5; design; extracellular vesicles; improved; in vivo; injured; insight; interdisciplinary approach; lung injury; macromolecule; member; mesenchymal stromal cell; multidisciplinary; nanomedicine; nanoparticle; nanoparticle delivery; nanoscale; novel; paracrine; pharmacologic; prevent; public health relevance; reconstitution; regenerative; success; synthetic construct; synthetic peptide; tissue injury

PROJECT SUMMARY The extracellular matrix in tissue is significantly disrupted in many disease conditions, but it is essential for cells to function. Endothelial cells become leaky when they no longer receive functional matrix signals upon tissue injury. Failure to restore endothelial barrier function can result in persistent edema, long-term tissue damage, and irreversible tissue fibrosis. Since many organs are highly vascularized, there is a need to find a general solution to treat tissue injury by restoring matrix-mediated signaling. There is currently no effective strategy to achieve this goal, since the activation of matrix signaling pathways requires the delivery of matrix molecules with proper molecular conformation and physiochemical properties. Here, we define a novel class of cell-secreted, non-vesicular nanoparticles that bear matrix molecules, which we call matrimeres. Our preliminary data show that mesenchymal stromal cells naturally secrete matrimeres consisting of fibronectin and DNA, which can directly activate endothelial cells to restore junctions disrupted by endotoxemia-induced injury. Importantly, we show that functional matrimeres can be reconstituted from purified fibronectin protein and genomic DNA fragments in a chemical environment similar to secretory compartments in cells. We will build on these results to test the hypothesis that fibronectin matrimeres treat tissue injury by restoring endothelial barrier function. In Aim 1, we will determine how fibronectin matrimeres restore endothelial barrier function after inflammatory injury in the lungs. In Aim 2, we will investigate biogenesis mechanisms of fibronectin matrimeres in mesenchymal stromal cells. In Aim 3, we will engineer synthetic matrimeres that restore endothelial barrier function. We predict that highly functional nanomedicine can be developed based on the fundamental insight that cells are able to recycle and repackage matrix molecules into nanoparticles by complexing with DNA fragments, which circulate in the body and play a homeostatic role in limiting vascular permeability. The project is highly multidisciplinary in that it will employ a combination of expertise in nanoscale biology, nanotechnology, chemical, biomaterials, computational, advanced imaging, cellular and molecular biology, and in vivo approaches to address the specific aims. The results will help develop a number of fundamental concepts of matrimeres in terms of their mechanisms of action, biogenesis, and reverse engineering. Success of the project will also enable the generalization of matrimeres as natural nanomedicine to deliver macromolecules for improved regenerative outcomes.

项目概要 在许多疾病条件下，组织中的细胞外基质被显着破坏，但它对于维持生命至关重要 细胞发挥功能。当内皮细胞不再接收功能性基质信号时，它们就会发生渗漏。 组织损伤。未能恢复内皮屏障功能可导致持续性水肿、长期组织 损伤和不可逆的组织纤维化。由于许多器官的血管化程度很高，因此需要找到一种 通过恢复基质介导的信号传导来治疗组织损伤的通用解决方案。目前尚无有效的 策略来实现这一目标，因为基质信号通路的激活需要基质的传递 具有适当分子构象和理化性质的分子。在这里，我们定义了一个新颖的类 细胞分泌的非囊泡纳米颗粒，带有基质分子，我们称之为基质分子。我们的 初步数据表明间充质基质细胞自然分泌由纤连蛋白组成的基质细胞 和DNA，它可以直接激活内皮细胞以恢复内毒素血症引起的破坏的连接 受伤。重要的是，我们证明功能性基质可以由纯化的纤连蛋白重建 和基因组 DNA 片段在类似于细胞分泌室的化学环境中。我们将 基于这些结果来检验纤连蛋白基质通过恢复来治疗组织损伤的假设 内皮屏障功能。在目标 1 中，我们将确定纤连蛋白基质如何恢复内皮屏障 肺部炎症损伤后的功能。在目标 2 中，我们将研究生物发生机制 间充质基质细胞中的纤连蛋白基质。在目标 3 中，我们将设计合成基质， 恢复内皮屏障功能。我们预测可以基于以下基础开发高功能纳米医学 细胞能够通过以下方式将基质分子回收并重新包装成纳米颗粒： 与 DNA 片段复合，在体内循环并在限制血管中发挥稳态作用 渗透性。该项目是高度多学科的，因为它将结合纳米级的专业知识 生物学、纳米技术、化学、生物材料、计算、高级成像、细胞和分子 生物学和体内方法来解决特定目标。研究结果将有助于开发一系列 基质的基本概念，包括其作用机制、生物发生和逆转 工程。该项目的成功还将促进基质作为天然纳米药物的推广 提供大分子以改善再生结果。