The epithelial matrisome and drug transport kinetics

上皮基质体和药物转运动力学

• 批准号: 10714617
• 负责人: Kaitlin C Fogg
• 金额: $ 35.31万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10714617
• 关键词: Address; Affect; Age; Binding; Biological Availability; Biological Process; Cell Polarity; Cell Proliferation; Chemicals; Circulation; Collection; Complement; Complex; Cues; Data Set; Disease; Drug Delivery Systems; Drug Transport; ECM receptor; Epithelium; Extracellular Matrix; Extracellular Matrix Proteins; Genes; Goals; Human; Image Analysis; Immune; In Vitro; Individual; Inflammation; Kinetics; Knowledge; Libraries; Localized Disease; Lung; Machine Learning; Maintenance; Mechanics; Menstrual cycle; Methods; Modeling; Molecular; Morphology; Oral; Organ; Permeability; Pharmaceutical Preparations; Phase; Prevention; Proteins; Proteome; Research; Role; Signal Transduction; Site; Skin; Statistical Models; Stratified Epithelium; Surface; Systemic disease; Systems Biology; Techniques; Tissue Engineering; Tissues; absorption; computerized tools; design; disease diagnosis; fibrous protein; hormonal signals; in vitro Model; migration; novel; novel therapeutics; programs; three-dimensional modeling; tool; Address; Affect; Age; Binding; Biological Availability; Biological Process; Cell Polarity; Cell Proliferation; Chemicals; Circulation; Collection; Complement; Complex; Cues; Data Set; Disease; Drug Delivery Systems; Drug Transport; ECM receptor; Epithelium; Extracellular Matrix; Extracellular Matrix Proteins; Genes; Goals; Human; Image Analysis; Immune; In Vitro; Individual; Inflammation; Kinetics; Knowledge; Libraries; Localized Disease; Lung; Machine Learning; Maintenance; Mechanics; Menstrual cycle; Methods; Modeling; Molecular; Morphology; Oral; Organ; Permeability; Pharmaceutical Preparations; Phase; Prevention; Proteins; Proteome; Research; Role; Signal Transduction; Site; Skin; Statistical Models; Stratified Epithelium; Surface; Systemic disease; Systems Biology; Techniques; Tissue Engineering; Tissues; absorption; computerized tools; design; disease diagnosis; fibrous protein; hormonal signals; in vitro Model; migration; novel; novel therapeutics; programs; three-dimensional modeling; tool

PROJECT SUMMARY The overarching goal of our research program is to couple computational tools with three-dimensional models of epithelial barriers to interrogate how the epithelial extracellular matrix (ECM) is influenced by extrinsic factors, how changes to the epithelial ECM affect drug delivery, and how the epithelial ECM can be harnessed to tailor drug bioavailability. Epithelial barriers are what lies between us and the outside world, serving as protective barriers and sites of selective permeability. For each type of epithelial tissue, each layer of stratified epithelium has its own unique ECM, a complex network of fibrous proteins that provides mechanical and chemical cues that drive cell proliferation, survival, differentiation, cell polarity, and migration. Dysregulation of epithelial barriers can be indicative of local or systemic disease and permeability of epithelial barriers directly affects how drug is delivered across the ECM and into the circulation. Recently, it has been appreciated that the ECM cannot be fully studied as the fibrous proteins alone, but instead should be evaluated as the interconnected network of proteins that make up the structural core of the ECM along with proteins that are critical to ECM function and maintenance such as receptors and ECM-bound soluble factors. This interconnected network has been defined as the matrisome, a curated collection of 1027 genes, roughly 4% of the known human proteome. While the roles of individual ECM proteins and ECM downstream signaling networks on epithelial function and permeability have been investigated, three key knowledge gaps persist: 1) How does the epithelial matrisome change with extrinsic factors such as age, menstrual cycle, and inflammation? 2) How do changes to the epithelial matrisome affect drug absorption and transport? 3) How can we modulate the epithelial matrisome for selective bioavailability? To address the first knowledge gap, in Project 1 we will evaluate publicly available datasets and biospecimens using our novel machine learning and image analysis techniques to reveal the interconnected relationships between matrisome changes and extrinsic factors such as age, menstrual cycle phase, and immune landscape. These studies will be complemented by orthogonal in vitro studies using our library of tissue engineered models that capture the layered morphology of epithelium. To address the second knowledge gap, in Project 2 we will couple our in vitro models with statistical modeling and systems biology tools to determine key matrisome proteins that influence drug delivery across epithelial surfaces and their corresponding mechanisms of action. Lastly, to address the third knowledge gap, in Project 3 we will identify novel compounds that modulate bioavailability through matrisome-driven mechanisms, opening new avenues of direction for the design and delivery of novel therapeutics with selective bioavailability. Critically, the methods that we are developing are tissue, organ, and disease agnostic, facilitating an increased understanding of a wide variety of biological processes at a molecular, cellular, and tissue level.

项目摘要 我们的研究计划的总体目标是将计算工具与三维模型息息 上皮壁垒的质疑上皮细胞外基质（ECM）如何受外在因素的影响， 上皮ECM的变化如何影响药物输送，以及如何利用上皮ECM量身定制 药物生物利用度。上皮障碍是我们与外界之间的所在，具有保护性 选择性渗透性的障碍和部位。对于每种类型的上皮组织，每层分层上皮 拥有自己独特的ECM，这是一个复杂的纤维蛋白网络，可提供机械和化学提示，这些线索 驱动细胞增殖，生存，分化，细胞极性和迁移。上皮屏障的失调可以 指示局部或全身性疾病以及上皮屏障的渗透性直接影响药物的方式 跨ECM传递到循环中。最近，人们对ECM不能是 仅作为纤维蛋白的纤维蛋白进行了全面研究，但应评估为 构成ECM结构核以及对ECM功能至关重要的蛋白质的蛋白质和 维护，例如受体和ECM结合的可溶性因子。该互连网络已定义 作为天生组，是1027个基因的策划集合，约占已知人类蛋白质组的4％。而 单个ECM蛋白和ECM下游信号网络的作用在上皮功能和渗透性上的作用 已经调查了三个关键知识差距持续存在：1）上皮矩阵如何随着 年龄，月经周期和炎症等外部因素？ 2）如何变化上皮矩阵 影响药物的吸收和运输？ 3）我们如何调节上皮矩阵的选择性 生物利用度？为了解决第一个知识差距，在项目1中，我们将评估公开可用的数据集和 使用我们的新机器学习和图像分析技术来揭示互连的生物测量 生成体变化与外部因素之间的关系，例如年龄，月经周期阶段和 免疫景观。这些研究将通过我们的组织库进行正交的体外研究补充 捕获上皮分层形态的工程模型。为了解决第二个知识差距， 在项目2中，我们将使我们的体外模型与统计建模和系统生物学工具相结合以确定 关键的生成蛋白会影响跨上皮表面递送药物及其相应的药物蛋白 作用机理。最后，为了解决第三个知识差距，在项目3中，我们将确定新颖的化合物 通过按母体驱动的机制来调节生物利用度，为该方向开辟了新的方向途径 具有选择性生物利用度的新型治疗剂的设计和交付。至关重要的是，我们的方法 发展是组织，器官和疾病的不可知论，促进了对各种各样的多种多样的了解 分子，细胞和组织水平的生物过程。