The epithelial matrisome and drug transport kinetics

项目摘要 我们研究计划的首要目标是将计算工具与三维模型相结合 的上皮屏障，以询问上皮细胞外基质（ECM）是如何受到外在因素的影响， 上皮细胞外基质的变化如何影响药物输送，以及如何利用上皮细胞外基质来定制 药物生物利用度上皮屏障是我们与外界之间的屏障， 屏障和选择性渗透的场所。对于每种上皮组织，每层复层上皮 有自己独特的ECM，一个复杂的纤维蛋白网络，提供机械和化学线索， 驱动细胞增殖、存活、分化、细胞极性和迁移。上皮屏障失调可 指示局部或全身性疾病，上皮屏障的渗透性直接影响药物如何 通过ECM进入循环。最近，已经认识到ECM不能被 作为纤维蛋白单独进行充分研究，但相反，应作为相互连接的网络进行评估， 构成ECM结构核心的蛋白质沿着对ECM功能至关重要的蛋白质， 维持，如受体和ECM结合的可溶性因子。这个互联的网络已经被定义为 作为基质体，它是1027个基因的精选集合，大约占已知人类蛋白质组的4%。而 单个ECM蛋白和ECM下游信号网络对上皮功能和通透性的作用 已经调查，三个关键的知识差距仍然存在：1）上皮基质体如何改变， 外在因素，如年龄、月经周期和炎症？2)上皮基质体的变化 影响药物的吸收和转运3)我们如何调节上皮基质体， 生物利用度？为了解决第一个知识缺口，在项目1中，我们将评估公开可用的数据集， 使用我们新颖的机器学习和图像分析技术， 基质体变化与年龄、月经周期、 免疫景观这些研究将通过使用我们的组织库的正交体外研究进行补充 工程模型捕捉上皮的分层形态。为了解决第二个知识差距， 在项目2中，我们将把我们的体外模型与统计建模和系统生物学工具结合起来， 影响药物通过上皮表面传递的关键基质体蛋白及其相应的 行动机制。最后，为了解决第三个知识缺口，在项目3中，我们将确定新的化合物 通过基质体驱动的机制调节生物利用度，为药物开发开辟了新的方向。 具有选择性生物利用度的新型治疗剂的设计和递送。关键是，我们的方法 发展是组织，器官和疾病不可知的，促进了对各种各样的疾病的理解。 在分子、细胞和组织水平上的生物过程。

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.