DYNAMICS UNDERLYING TISSUE INTEGRITY

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 研究中心，而研究中心不一定是研究者所在的机构。 该项目旨在解决组织完整性的机制。我们把组织看作是相互作用的细胞和基质的网络。我们假设，组织完整性的结果，从不同的细胞类型和这些细胞结合在一起的矩阵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，我们将重点放在肾小球滤过屏障。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循环之间的连续信息流导致三个实体整合成一个单一的内聚功能结构：过滤屏障。这种信息既有化学的（分泌的自分泌/旁分泌因子和细胞/细胞和细胞/基质接触），也有物理的（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中的细胞内信号传导网络无缝整合，以引起动态维持三节点环的反应，从而导致组织完整性和功能性。为了测试这些想法，我们将合并3D计算模型，纳米到微米级的3D制造和纳米图案化耦合到微流体设备，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活细胞成像来测量由重组组织的组分之间的相互作用产生的信息流的动态，所述重组组织引起装置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，这些原则有助于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.