A Microphysiological System for Kidney Disease Modeling and Drug Efficacy Testing

项目摘要 慢性肾脏疾病是一种公共卫生问题，影响着美国2000多万成年人。 人口，是第九大死因。除肾素-血管紧张素系统抑制剂外， 减缓肾脏疾病的进展，降低死亡率，或改善人们的生活质量。新 针对这些潜在疾病的早期阶段的策略对于改善 结果和患者护理。促进安全有效的药物开发， 由于肾脏疾病，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寻常的三重生理 以肾小球过滤、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的能力， 疾病传统的二维人类上皮细胞模型不能准确地再现肾脏 微流体流动对于肾脏肾单位的结构和功能是必不可少的，并且是一种 在再现体内生理学和病理生理学中的基本成分。我们开发了一个三 三维流动导向的“芯片上的肾”微生理系统， 其已通过对关键组件结构的功能表征进行了广泛测试， 近端小管和管周微血管网。我们还能够常规地获得、分离和 表征多种人肾细胞谱系的相对纯的原代培养物。另外我们有 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 当人肾细胞在该基质中生长时，显示出表型差异。另外我们有 最近将人类多能干细胞与基因编辑技术结合使用， MPS。我们的平台允许精确控制细胞组成、细胞外基质和血管， 管状几何形状和流动。该应用的目标是对重要的人类肾脏疾病进行建模， 促进确定安全和有效的治疗方法。为了达到这个目标，我们设立了一个 具有肾脏生理学和病理学、细胞和分子生物学专业知识的多学科调查团队 生物学，系统药理学和毒理学，生物标志物发现和评价，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，最终在 概括肾脏生理功能、损伤反应和修复关键方面的体外模型 可以极大地促进药物发现和开发，并最终实现“虚拟临床试验” 用于候选疗法。

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.