Development of a BBB model to study transendothelial cell migration

开发 BBB 模型来研究跨内皮细胞迁移

• 批准号: 8537506
• 负责人: DAMIR JANIGRO
• 金额: $ 47.07万
• 依托单位: FLOCEL, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8537506
• 关键词: Achievement; Anti-Inflammatory Agents; Anti-inflammatory; Arts; Biological; Blood - brain barrier anatomy; Blood Vessels; Blood capillaries; Brain; Brain Diseases; Cell Line; Characteristics; Clinical; Coculture Techniques; Contracts; Data; Development; Disease; Drug resistance; Economics; Endothelial Cells; Epilepsy; Experimental Designs; Extravasation; Fee-for-Service Plans; Fiber; Human; Immune response; In Vitro; Inflammatory; Knowledge; Leukocyte Trafficking; Leukocytes; Mechanics; Mediation; Modality; Modeling; Multiple Sclerosis; Neuroglia; Pathologic; Pattern; Performance; Pericytes; Permeability; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Phase; Physiological; Physiology; Process; Progress Reports; Property; Protocols documentation; Publishing; Recording of previous events; Reproduction; Research Personnel; Rest; Rodent; Role; Scanning Electron Microscopy; Side; Signal Transduction; Small Business Technology Transfer Research; Smooth Muscle Myocytes; Stimulus; Stretching; System; Test Result; Testing; Traction; base; capillary; cell motility; chemokine; clinically relevant; commercialization; design; drug development; drug testing; drug use screening; hemodynamics; improved; in vitro Model; insight; migration; monocyte; nervous system disorder; novel; pre-clinical; prototype; research and development; research study; response; scale up; shear stress; sound; success; therapeutic target; venule

DESCRIPTION (provided by applicant): Reproducing in vitro the physiological characteristics of brain vascular segments represents a critical issue. Adequate modeling of the cerebrovasculature could significantly help understand the mechanisms and improve the pharmacology of disease where a role for leukocytes migrating across the cerebrovasculature is demonstrated. Thanks to the previous support (Phase I) we were able to prototype and test drive a new dynamic in vitro model of the BBB (DIV- BBB) permissive for leukocyte extravasation. Our initial effort aimed at piercing hollow fibers in a reproducible manner; the results were recently published. We found that manually perforated hollow fibers allow leukocytes passage across the BBB in response to pro-inflammatory stimuli and hemodynamic changes. We were also able to produce a capillary-venule segment by varying the rheological parameters (e.g., changing the shear stress) of the system. In addition we recently developed a system to mechanically "stretch" the hollow fibers increasing the pore size up to the physiologically relevant size of ~5 ¿m. Controlled traction was applied to the end of the fibers and scanning electron microscopy showed enlarged pores within the stretched fiber. To further the commercial opportunity afforded by this new BBB model, we propose the following Phase II Specific Aims: To optimize the performance of a dynamic in vitro capillary-venules model of the brain cerebrovasculature permissive for leukocyte extravasation. To determine the pattern of leukocytes extravasation in control and diseased capillary-venules segments composed of fibers with different transmural permeability properties (from Aim 1). To compare the results obtained using these DIV- BBB models to other state-of-art in vitro BBB models. We will initially tailor the use of the DIV capillary-venules system to multiple sclerosis and epilepsy research and drug development. We have assembled a multi-disciplinary team of investigators and experts in the field of leukocyte migration across the cerebrovasculature. Additional clinically relevant venues are detailed in the Commercialization Plan. Given our preliminary results and the confirmatory progress report described in detail in this application, and given the fact that i the meantime development of new drugs has remained a major issue in the treatment of neurological diseases, we believe that the combination of a strong record of accomplishment and sound experimental design aimed at improving drug development are fundamental aspects of this Phase 2 proposal.

描述（由适用提供）：在体外重现脑血管段的物理特征是一个关键问题。对脑血管造期的足够建模可以显着帮助理解机制并改善疾病的药理学，在这些疾病的药理学中，在脑桥腔迁移的白细胞作用中的作用得到了证明。感谢先前的支持（I阶段），我们能够原型和测试驱动BBB（DIV-BBB）允许白细胞渗出的新动态体外模型。我们最初的努力旨在以可重复的方式刺穿空心纤维；结果最近发表了。我们发现，手动穿孔的空心纤维可以响应促炎性刺激和血液动力学变化，使白细胞穿过BBB。我们还能够通过改变系统的流变学参数（例如改变剪切应力）来产生毛细血管段段。此外，我们最近开发了一个系统，可以机械地“伸展”空心纤维，从而将孔径增加到〜5€的物理相关尺寸。将受控的牵引力应用于纤维的末端，扫描电子显微镜在拉伸纤维内增加了孔。为了进一步提供这种新的BBB模型提供的商业机会，我们提出了以下II阶段的特定目的：优化脑大脑大脑脑脑体外毛细血管模型的动态性毛细血管模型，以允许白细胞散发性。确定白细胞在对照和患病的毛细血管呈段段中的渗出的模式，由具有不同变化性渗透性特性的纤维组成（来自AIM 1）。为了比较使用这些Div-BBB模型获得的结果与其他最新的体外BBB模型。我们最初将调整DIV毛细血管系统的使用来进行多发性硬化症和癫痫研究和药物开发。我们已经组建了一个在脑桥一次的白细胞迁移领域的研究人员和专家组成的多学科团队。商业化计划中详细介绍了其他与临床相关的场所。鉴于我们的初步结果以及本应用程序中详细描述的确认进度报告，并且鉴于我的意思是新药的时间开发仍然是治疗神经疾病的主要问题，因此我们认为，旨在改善药物开发的良好成就记录和合理的实验设计的结合是这一阶段2提案的基本方面。