Dynamics Underlying Tissue Integrity

组织完整性的动力学

• 批准号: 8333909
• 负责人: John Cijiang He
• 金额: $ 135.35万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-21 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8333909
• 关键词: Address; Advanced Malignant Neoplasm; Angiotensin-Converting Enzyme Inhibitors; Area; Behavior; Binding; Biological Models; Cardiovascular Diseases; Cells; Chemicals; Complex; Computer Simulation; Coupled; Devices; Disease; Disease Progression; Dopamine Receptor; Drug Delivery Systems; Endothelial Cells; Engineering; Environment; Enzymes; Event; Extracellular Matrix; Filtration; Functional disorder; Genes; Genotype; Goals; Heart Hypertrophy; Heart failure; Human; Hypertension; In Vitro; Individual; Injury; Kidney; Kidney Diseases; Kidney Failure; Lead; Life; Malignant Neoplasms; Mammals; Measures; Mechanics; Methods; Microfluidic Microchips; Molecular; Mutation; Natural regeneration; Neoplasm Metastasis; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Organ; Organism; Paralysed; Pharmaceutical Preparations; Phenotype; Physiological; Process; Proteins; Proteinuria; Role; Science; Screening procedure; Signal Transduction; Source; Specific qualifier value; Structure; System; Testing; Therapeutic; Tissue Model; Tissues; autocrine; base; biomedical scientist; cell type; cellular imaging; design; glomerular basement membrane; glomerular filtration; injured; kidney cortex; mathematical model; multidisciplinary; nano; nanopattern; paracrine; podocyte; receptor; reconstitution; response

Project Summary 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 3D- computational 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.

项目概要 该项目旨在解决组织完整性的潜在机制。我们将组织视为相互作用的细胞和基质的网络。我们假设组织完整性是由不同细胞类型和结合这些细胞的基质之间的动态相互作用产生的信息整合产生的 一起。为了检验这一假设，我们将重点关注肾脏肾小球滤过屏障。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会导致这三个实体整合成一个单一的内聚功能结构：过滤屏障。这些信息都是化学的（分泌的自分泌/旁分泌 因素和细胞/细胞和细胞/基质接触）和物理（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的细胞内信号网络无缝集成，以激发动态维持三节点环路的反应，从而实现组织的完整性和功能性。为了测试这些想法，我们将合并 3D- 计算模型、纳米到微米级 3D 制造和纳米图案耦合到微流体装置，以在工程装置内重建过滤屏障。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组件之间的相互作用产生的信息流动态，这些组件在设备内产生肾小球滤过屏障。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，从而有助于了解疾病过程和筛选新药。