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.

项目摘要 组织中的细胞外基质在许多疾病条件下被显著破坏，但它对于维持细胞内基质的稳定性是必需的。 细胞功能。当内皮细胞不再接收功能性基质信号时， 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。由于许多器官是高度血管化的，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一般解决方案。目前尚无有效 实现这一目标的策略，因为基质信号通路的激活需要基质的递送。 具有适当的分子构象和物理化学性质的分子。在这里，我们定义了一个新的类， 细胞分泌的，非囊泡的纳米颗粒，带有基质分子，我们称之为基质粒。我们 初步数据显示间充质基质细胞天然分泌由纤连蛋白组成的基质 和DNA，它可以直接激活内皮细胞，以恢复被内毒素血症诱导的 损伤重要的是，我们发现功能性基质可以从纯化的纤连蛋白质中重建， 和基因组DNA片段在类似于细胞中的分泌区室的化学环境中。我们将 基于这些结果来检验纤连蛋白基质通过修复组织损伤来治疗组织损伤的假设。 内皮屏障功能在目标1中，我们将确定纤维连接蛋白基质如何恢复内皮屏障 在肺部炎症损伤后的功能。在目标2中，我们将研究 间充质基质细胞中的纤维连接蛋白基质。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，高功能的纳米医学可以开发基于 基本的见解是，细胞能够回收和重新包装基质分子进入纳米颗粒， 与DNA片段复合，DNA片段在体内循环并在限制血管生成中发挥稳态作用。 磁导率该项目是高度多学科的，因为它将采用纳米级的专业知识相结合， 生物学、纳米技术、化学、生物材料、计算、先进成像、细胞和分子 生物学和体内方法来解决特定的目标。研究结果将有助于开发一些 关于母体的作用机制、生物发生和逆转的基本概念 工程.该项目的成功也将使matrimeres作为天然纳米医学的推广成为可能 来输送大分子以改善再生效果。