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

基本信息

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
项目类别：
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

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

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项目摘要

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.

项目摘要慢性肾脏病是一个公共卫生问题，影响了美国成年人超过2000万人人口，是死亡的第九大原因。除肾素 - 血管紧张素系统抑制剂以外，很少有药物减慢肾脏疾病的进展，降低死亡率或改善人们生活质量。新的针对这些基本疾病早期阶段的策略对于改善根本上很重要结果和患者护理。催化安全有效治疗的药物的开发肾脏疾病，至关重要的是能够在体外对人类肾脏疾病进行建模和体外受伤临床前药物开发。复杂的多细胞体系结构和不寻常的生理三合会以肾小球滤过，管状分泌和管状重吸附为特征的过程通常具有限制整个生物体模型充分概括人类多样性和表现的能力疾病。常规的二维人上皮细胞模型不能准确概括肾脏生理学或疾病，微流体流对于肾脏肾单位的结构和功能至关重要，并且是一种概括体内生理学和病理生理学的基本组成部分。我们已经开发了三个尺寸流针对人类肾细胞的“芯片上的肾脏”微生物生理系统，通过对关键组件结构的功能表征进行了广泛的测试近端管和周围的微血管网络。我们还能够逐渐获得，分离和表征多个人类肾细胞谱系的相对纯粹的原发性培养物。此外，我们还有开发的水凝胶由脱细胞的人肾皮质外基质和当该基质中人类肾细胞生长时，表现出表型差异。此外，我们还有最近纳入了人类多能干细胞以及基因编辑技术的使用国会议员。我们的平台可以精确控制细胞组成，细胞外基质和血管和血管和块茎几何和流动。该应用的目的是建模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，我们已经建立了具有肾脏生理学和病理学专业知识的多学科调查团队，细胞和分子生物学，系统药理学和毒理学，生物标志物发现与评估，生物医学工程，微流体，基质生物学，基因组学，计算生物学和生物统计学。如果成功，最终概括肾脏生理功能的关键方面的体外模型，对损伤的反应和修复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” 用于候选治疗。