Therapeutic nanoscale matrimeres

项目总结 组织中的细胞外基质在许多疾病情况下都会受到严重破坏，但它对 细胞才能发挥作用。当内皮细胞不再接收到功能性基质信号时，它们就会变得漏液 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 损伤和不可逆转的组织纤维化。由于许多器官是高度血运的，因此有必要找到一种 通过恢复基质介导的信号来治疗组织损伤的一般解决方案。目前还没有有效的 实现这一目标的策略，因为激活基质信号通路需要递送基质 具有适当的分子构象和物理化学性质的分子。在这里，我们定义了一类新的 细胞分泌的、非泡状的纳米颗粒，带有基质分子，我们称之为基质分子。我们的 初步数据显示，间充质基质细胞自然分泌由纤维连接蛋白组成的基质。 以及DNA，它可以直接激活内皮细胞，恢复内毒素血症引起的连接中断 受伤。重要的是，我们证明了功能基质可以从纯化的纤维连接蛋白重组而来。 和基因组DNA片段在类似于细胞分泌室的化学环境中。我们会 基于这些结果，验证纤维连接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修复内皮屏障。 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维连接蛋白基质。在目标3中，我们将设计合成母体 恢复内皮屏障功能。我们预测，高功能的纳米医学可以基于 细胞能够回收基质分子并将其重新包装成纳米颗粒的基本见解是通过 与DNA片段络合，DNA片段在体内循环，在限制血管方面起到平衡作用 渗透性。该项目是高度多学科的，因为它将采用纳米级专业知识的组合。 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，以解决特定的目标。这一结果将有助于制定一系列 关于基质作用机制、生物发生和逆转的基本概念 工程学。该项目的成功还将使基质作为天然纳米药物得到推广。 传递大分子以改善再生效果。

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.