A Microphysiological System for Kidney Disease Modeling and Drug Efficacy Testing

项目摘要 慢性肾脏疾病是一个公共健康问题，在美国成年人中有2000多万人受到影响 人口，是第九大致死原因。除肾素-血管紧张素系统抑制剂外几乎没有其他药物 延缓肾脏疾病的发展，降低死亡率，或提高人们的生活质量。新的 针对这些潜在疾病的早期阶段的战略对改善 结果和病人护理。促进安全有效的治疗药物的开发 肾脏疾病，迫切需要能够在体外模拟人类肾脏疾病和损伤 临床前药物开发。复杂的多细胞结构和不同寻常的生理三位一体 以肾小球滤过、肾小管分泌和肾小管重吸收为特征的过程通常 限制了整个生物体模型完全概括人类多样性和表现形式的能力 疾病。传统的二维人类上皮细胞模型不能准确地概括肾脏 生理或疾病，以及微流控流对肾单位的结构和功能是必不可少的，是一种 概述体内生理学和病理生理学的基本成分。我们已经开发出了三个 维流导向的植入人肾细胞的“芯片上肾脏”微生理系统， 它已经通过对关键组件结构的功能表征进行了广泛的测试 近端小管和肾小管周围微血管网。我们还能够例行公事地获取、隔离和 鉴定多个人类肾脏细胞系的相对纯净的原代培养。此外，我们还有 开发了由脱细胞的人肾皮质细胞外基质组成的水凝胶，以及 显示了人类肾脏细胞在这种基质中生长时的表型差异。此外，我们还有 最近将人类多能干细胞的使用与基因编辑技术结合到我们的 国会议员。我们的平台允许精确控制细胞成分、细胞外基质和血管及 管状几何图形和流动。这个应用程序的目标是模拟重要的人类肾脏疾病和 促进安全有效治疗的识别。为了实现这一目标，我们建立了一个 具有肾脏生理学和病理学、细胞和分子方面专业知识的多学科研究团队 生物学、系统药理学和毒理学、生物标记物的发现和评估、生物医学工程、 微流体学、基质生物学、基因组学、计算生物学和生物统计学。如果成功，最终将在 概述肾脏生理功能、损伤反应和修复的关键方面的体外模型 可极大地促进药物的发现和开发，并可最终实现“虚拟临床试验”。 候选治疗学。

Project Summary Chronic kidney disease is a public health problem affecting more than 20 million people in the US adult population, and is the 9th leading cause of death. Few drugs other than renin-angiotensin system inhibitors slow the progression of kidney disease, lower mortality rates, or improve quality of life among people. New strategies targeting the early stages of these underlying diseases are fundamentally important to improve outcomes and patient care. To catalyze the development of drugs that are safe and effective for treating kidney diseases, there is a critical need to be able to model human kidney diseases and injury in vitro during preclinical drug development. The complex multicellular architecture and unusual triad of physiological processes characterized by glomerular filtration, tubular secretion and tubular reabsorption, have often limited the ability of whole organism models to fully recapitulate the diversity and manifestations of human disease. Conventional two-dimensional human epithelial cell models do not accurately recapitulate kidney physiology or disease, and microfluidic flow is essential to kidney nephron structure and function, and is an essential component in recapitulating in vivo physiology and pathophysiology. We have developed a three dimensional flow directed “kidney-on-a-chip” microphysiological system populated with human kidney cells, which has been extensively tested with functional characterization of key component structures of the proximal tubule and the peritubular microvascular network. We are also able to routinely obtain, isolate and characterize relatively pure primary cultures of multiple human kidney cell lineages. In addition, we have developed hydrogels consisting of decellularized human kidney cortical extracellular matrix, and demonstrated phenotypic differences when human kidney cells are grown in this matrix. In addition, we have recently incorporated the use of human pluripotent stem cells coupled with gene editing techniques into our MPS. Our platforms allow for precise control of cellular composition, extracellular matrix, and vascular and tubular geometry and flow. The goal of this application is to model important human kidney diseases and promote identification of safe and effective treatments. To achieve this goal, we have established a multidisciplinary investigative team with expertise in kidney physiology and pathology, cellular and molecular biology, systems pharmacology and toxicology, biomarker discovery and evaluation, biomedical engineering, microfluidics, matrix biology, genomics, computational biology, and biostatistics. If successful, ultimately in vitro models that recapitulate critical aspects of kidney physiological function, response to injury, and repair could contribute greatly to drug discovery and development, and could ultimately enable `virtual clinical trials' for candidate therapeutics.