DYNAMICS UNDERLYING TISSUE INTEGRITY

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 该项目寻求解决潜在的组织完整性的机制。我们认为组织是相互作用的细胞和基质的网络。我们假设，组织的完整性源于不同细胞类型和将这些细胞结合在一起的基质之间的动态相互作用所产生的信息的整合。为了验证这一假设，我们将重点研究肾小球滤过屏障。在这个系统中，我们预测由足细胞、肾小球基底膜和内皮细胞组成的三节点环路之间的连续信息流导致这三个实体整合到一个单一的粘合功能结构：滤过屏障。这种信息既是化学的(分泌的自分泌/旁分泌因子以及细胞/细胞和细胞/基质接触)，也是物理的(细胞/细胞和细胞/基质接触产生的力)。来自物理和化学来源的信息通过足细胞和内皮细胞内的细胞内信号网络无缝整合，以唤起动态维持三结点环路的反应，导致组织的完整性和功能。为了测试这些想法，我们将合并3D计算模型、纳米到微米尺度的3D制造以及耦合到微流控设备的纳米喷雾，以重建工程设备内的过滤屏障。我们将使用信号相互作用的实时细胞成像来测量由重组组织的组件之间的相互作用产生的信息流的动力学，这些相互作用导致设备内的肾小球滤过屏障。预计这些研究将使我们能够确定组装功能组织的一般设计原则，这些组织可以帮助理解疾病过程和筛选新药。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This project seeks to address the mechanisms underlying tissue integrity. We view tissue as networks of interacting cells and matrices. We hypothesize that tissue integrity results from the integration of information that arises from the dynamic interactions between the different cell types and the matrices that bind these cells together. To test this hypothesis we will focus on the kidney glomerular filtration barrier. In this system we predict that continuous information flow between a three-node loop consisting of podocytes cells, glomerular basement membrane and endothelial cells results in integrating the three entities into a single cohesive functional structure: the filtration barrier. Such information is both chemical (secreted autocrine /paracrine factors and cell/cell and cell/matrix contacts) and physical (forces arising from cell/cell and cell/matrix contacts). The information from physical and chemical sources is seamlessly integrated by intracellular signaling networks in the podocytes and endothelial cells to evoke responses that dynamically sustain the three-node loop, resulting in tissue integrity and functionality. To test these ideas we will merge 3Dcomputational models, nano-to-micro scale 3D fabrication and nanopatterning coupled to microfluidic devices to reconstitute a filtration barrier within the engineered device. We will use live cell imaging of signaling interactions to measure the dynamics of information flow arising from interactions between components of the reassembled tissue that give rise to the glomerular filtration barrier within the device. It is anticipated that these studies will allow us to identify general design principles to assemble functional tissues that can aid in understanding disease processes and for screening for new drugs.