An engineered platform for the study of metastasis (PQ #24)

用于研究转移的工程平台（PQ

• 批准号: 8677827
• 负责人: Peter C Searson
• 金额: $ 32.15万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8677827
• 关键词: Address; Adhesions; Aluminum; Animal Model; Biologic Characteristic; Biological; Biology; Blood Vessels; Caliber; Cardiovascular system; Cells; Cessation of life; Chemicals; Clinical; Cytoskeleton; Data; Development; Disease; Distant; Endothelial Cells; Engineering; Event; Extracellular Matrix; Extravasation; Foundations; Geometry; Goals; Growth Factor; Image; Laboratories; Malignant Neoplasms; Microfluidics; Modeling; Molds; Neoplasm Metastasis; One-Step dentin bonding system; Online Systems; Outcome; Perfusion; Physics; Primary Neoplasm; Process; Property; Protocols documentation; Research; Signaling Molecule; Site; Solutions; Structure; Time; Tissue Engineering; Tissue Grafts; Tissues; Translating; Translations; Tumor Biology; Vascular Endothelial Cell; Vascular System; Viscosity; angiogenesis; anticancer research; cancer cell; cancer imaging; cell type; chemical property; design; insight; meetings; metastatic process; migration; mortality; novel strategies; prevent; research study; stem; success; tumor

DESCRIPTION (provided by applicant): This application addresses PQ #24: Given the difficulty of studying metastasis, can we develop new approaches, such as engineered tissue grafts, to investigate the biology of tumor spread? Many of the steps in the metastatic process, specifically invasion, intravasation, and extravasation, take place at or near the interface between the local tissue microenvironment and the vascular system. Therefore the development of a platform that combines both extracellular matrix and a vessel is key to unraveling the events that guide the development of metastasis. The major challenge in developing such a platform is the complexity of this interface. To address this challenge we propose a microfluidic platform that incorporates both artificial extra cellular matrix and a vessel. Our objective is to produce a platform that: (1) recapitulates the relevant physical and biological characteristics of the interface between extracellular matrix and a vessel in a physiologically relevant geometry, (2) allows control over physicochemical and biological properties such that experiments can be performed systematically and reproducibly, and allowing variables to be adjusted independently, and (3) is sufficiently robust that fabrication can be readily translated to other laboratories. In preliminary data we have demonstrated fabrication of a functional platform and the feasibility of using the platform to study metastasis. In this research, we propose to lay the foundations for the refinement and further development of the platform to enable advances in the understanding of metastasis. The artificial extra cellular matrix/vessel platform allows study of invasion, intravasation and extravasation in a physiologically relevant geometry. To study invasion and intravasation a cavity is created in the extra cellular matrix near the artificial vessel. Prolifertion, detachment, and migration of cancer cells to the vessel, followed by intravasation into the vessel, can be imaged in real time. To study extravasation, cancer cells are added to the perfusion media flowing through the vessel. Depending on the vessel size, arrest can occur by adhesion or occlusion. In preliminary data, we have performed a proof-of-principle demonstration of the formation of a perfused artificial vessel using vascular endothelial cells and the incorporation of a tumor for the study of invasion and intravasation. The overall goal of this project is to develop an engineered ECM/vessel platform for the systematic study of key steps in the metastatic cascade. Building on these results we will optimize the engineered ECM/vessel platform (Aim 1), study the dynamics of invasion and intravasation (Aim 2a) and extravasation (Aim 2b), and develop modules for the translation of the engineered ECM/vessel platform for the study of metastasis (Aim 3).

描述（由申请人提供）：此申请地址PQ＃24：考虑到研究转移的困难，我们可以开发新方法，例如工程组织移植物，以研究肿瘤扩散的生物学？转移过程中的许多步骤，特别是入侵，侵入和外渗，发生在局部组织微环境和血管系统之间的接口或附近。因此，结合细胞外基质和容器的平台的发展是揭示指导转移发展的事件的关键。开发此类平台的主要挑战是该界面的复杂性。为了应对这一挑战，我们提出了一个微流体平台，该平台既结合了人造额外的细胞基质和容器。我们的目标是产生一个平台：（1）概括细胞外基质和在生理相关的几何形状中的界面和血管之间界面的相关物理和生物学特征（2），可以控制物理化学和生物学特性，例如，实验可以进行系统地和易于启动，并可以易于启动，并可以易于启动，并具有独立性的形式，并且可以独立地进行，并且可以进行4. 3. 3. 3.翻译成其他实验室。在 初步数据我们已经证明了功能平台的制造以及使用平台研究转移的可行性。在这项研究中，我们建议为平台的完善和进一步发展奠定基础，以使人们能够理解转移。人工额外的细胞基质/血管平台可以研究生理相关的几何形状中的入侵，侵入和渗出。为了研究侵袭和侵入，在人造血管附近的额外细胞基质中产生了一个腔。可以实时成像，癌细胞向血管的增殖，脱落和迁移，然后侵入血管。为了研究渗出，将癌细胞添加到流过血管的灌注培养基中。根据容器的大小，可以通过粘附或遮挡发生逮捕。在初步数据中，我们对使用血管内皮细胞和 将肿瘤纳入研究和侵入研究。该项目的总体目标是开发一个工程的ECM/船只平台，以系统地研究转移级联的关键步骤。在这些结果的基础上，我们将优化工程的ECM/船只平台（AIM 1），研究入侵和侵入的动态（AIM 2A）和渗出（AIM 2B），并开发用于转化ECM/船只平台的模块，以研究转移（AIM 3）。