A Microphysiological System for Kidney Disease Modeling and Drug Efficacy Testing

用于肾脏疾病建模和药效测试的微生理系统

• 批准号: 9975953
• 负责人: Jonathan Himmelfarb
• 金额: $ 119.05万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-25 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9975953
• 关键词: 3-Dimensional; Address; Adult; Affect; Animal Model; Apolipoproteins; Architecture; Aristolochic Acids; Atrophic; Autosomal Recessive Polycystic Kidney; Balkan Nephropathy; Biology; Biomedical Engineering; Biomedical Research; Biometry; Biomimetics; Blood Vessels; Blood capillaries; Cause of Death; Cell Lineage; Cell model; Chinese Herbs; Chronic Kidney Failure; Clinical Trials; Clinical Trials Design; Complex; Computational Biology; Coupled; Cyclosporine; Development; Disease; Disease Progression; Disease model; Epithelial Cells; Etiology; Exposure to; Extracellular Matrix; Fibrosis; Foundations; Functional disorder; Genes; Genomics; Geometry; Goals; Health; Human; Hydrogels; In Vitro; Injury to Kidney; Internal Medicine; Kidney; Kidney Diseases; Mediating; Microfluidics; Modeling; Modernization; Molecular; Molecular and Cellular Biology; Nephrology; Nephrons; Pathogenesis; Pathology; Patient Care; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology and Toxicology; Phase; Phenotype; Physiological; Physiological Processes; Physiology; Population; Preclinical Drug Development; Public Health; Publishing; Quality of life; Randomized Clinical Trials; Renin-Angiotensin System; Research; Science; Shiga Toxin; Structure; System; Tacrolimus; Techniques; Testing; Therapeutic; Toxic Environmental Substances; Toxic effect; Toxicity Tests; Translating; Triad Acrylic Resin; Tubular formation; Whole Organism; biomarker discovery; biomarker evaluation; drug candidate; drug development; drug discovery; drug efficacy; effective therapy; efficacy testing; glomerular filtration; human disease; human model; human pluripotent stem cell; improved; improved outcome; in vitro Model; in vivo; inhibitor/antagonist; injury and repair; interstitial; kidney cell; medical specialties; microfluidic technology; microphysiology system; mortality; multidisciplinary; nephrotoxicity; novel therapeutics; pathogen; pre-clinical; response to injury; side effect; therapeutic candidate; two-dimensional; virtual; virtual clinical trial

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.

项目概要 慢性肾病是影响超过 2000 万美国成年人的公共卫生问题 人口，是第九大死因。除肾素-血管紧张素系统抑制剂外很少有药物 减缓肾脏疾病的进展，降低死亡率，或提高人们的生活质量。新的 针对这些基础疾病早期阶段的策略对于改善 结果和患者护理。促进安全有效治疗药物的开发 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寻常的生理三联体 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 限制了整个有机体模型充分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 生理或疾病，微流体流动对于肾单位的结构和功能至关重要，并且是 概括体内生理学和病理生理学的重要组成部分。我们开发了三 维度流引导的“芯片上的肾脏”微生理系统，填充有人类肾细胞， 它已经过对关键部件结构的功能表征进行了广泛的测试 近端肾小管和肾小管周围微血管网络。我们还能够定期获得、分离和 表征多个人肾细胞谱系的相对纯的原代培养物。此外，我们还有 开发了由脱细胞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表现出表型差异。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研究中 MPS。我们的平台可以精确控制细胞组成、细胞外基质以及血管和 管状几何形状和流动。该应用程序的目标是模拟重要的人类肾脏疾病和 促进安全有效的治疗方法的确定。为了实现这一目标，我们建立了 具有肾脏生理学和病理学、细胞和分子专业知识的多学科研究团队 生物学、系统药理学和毒理学、生物标志物发现和评估、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。如果成功的话，最终会在 概括肾脏生理功能、损伤反应和修复的关键方面的体外模型 可以为药物发现和开发做出巨大贡献，并最终可以实现“虚拟临床试验” 候选疗法。