Using iPSCs to model patient outcomes in nephrotic syndrome

使用 iPSC 模拟肾病综合征患者的预后

• 批准号: 9264737
• 负责人: Jonathan Himmelfarb
• 金额: $ 16.84万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-24 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9264737
• 关键词: 3-Dimensional; Acute Renal Failure with Renal Papillary Necrosis; Adult; Affect; Biological Models; Biology; Biomedical Engineering; Blood Vessels; Cell physiology; Cells; Cellular Structures; Chronic Kidney Failure; Complex; Coupled; Data; Development; Disease; Drug toxicity; Enzymes; Epithelial Cells; Excretory function; Goals; Health; Human; In Vitro; Individual; Injury to Kidney; Intestines; Investigation; Kidney; Kidney Diseases; Knowledge; Link; Liver; Medicine; Metabolic Pathway; Metabolism; Modeling; Molecular; Molecular and Cellular Biology; Nephrotic Syndrome; Organ; Pathway interactions; Patient-Focused Outcomes; Pharmaceutical Preparations; Phase; Physiology; Play; Population; Principal Investigator; Process; Public Health; Renal clearance function; Renal tubule structure; Research; Research Personnel; Resources; Role; Safety; System; Systems Biology; Tissue Engineering; Tissues; Toxic effect; Toxicity Tests; Toxicology; Tubular formation; Work; Writing; Xenobiotics; base; body system; drug candidate; drug development; drug efficacy; efficacy evaluation; improved; improved functioning; induced pluripotent stem cell; interstitial; kidney cell; multidisciplinary; pharmacokinetic model; programs; response; solute

DESCRIPTION (provided by applicant): There is a critical need to be able to model human organ systems, such as the kidney, to improve our understanding of drug efficacy, safety, and toxicity, especially during drug development. The kidneys in general and the proximal tubule specifically, play a central role in the elimination of xenobiotics. With recent advances in molecular investigation, considerable information has been gathered regarding the substrate profiles of the individual transporters expressed in the proximal tubule. However, we have little knowledge of how these transporters coupled with intracellular enzymes and influenced by metabolic pathways form an efficient secretory and reabsorptive mechanism in the renal tubule. Moreover, while kidney disease is a public health problem that affects more than 27 million people in the US adult population, little is understood about the impact of kidney disease on drug disposition. The goal of this application is to develop a model system that predicts drug excretion by the human kidney, emulating healthy and disease related conditions. We propose to robustly model the human kidney utilizing an in vitro 3-dimensional modular microphysiological system with human kidney-derived cells. The microphysiological system will accurately reflect human physiology, be usable to predict renal handling of xenobiotics, and will assess response to kidney injury from endogenous and exogenous intoxicants. We also propose to work closely with other investigators in order to ultimately link our kidney module with other organ or tissue modules to achieve a 'systems biology and medicine' approach in the UH3 phase. To achieve this goal, we have established a multidisciplinary investigative team with expertise in kidney based cellular and molecular biology, renal toxicology, pharmacokinetic modeling, vascular biology, and biomedical engineering. This will create a unique resource of great utility for the UH2/UH3 Consortium. The proposed research plan, by improving our understanding of the determinants of xenobiotic excretion by modeling kidney cell function in health and disease, has the potential to dramatically impact the public health.

描述（由申请人提供）：迫切需要能够模拟人体器官系统，如肾脏，以提高我们对药物疗效，安全性和毒性的理解，特别是在药物开发期间。一般而言，肾脏和近端小管在消除外源性物质中起着核心作用。随着分子研究的最新进展，已经收集了大量关于近端小管中表达的单个转运蛋白的底物分布的信息。然而，我们对这些转运蛋白如何与细胞内酶偶联并受代谢途径的影响在肾小管中形成有效的分泌和重吸收机制知之甚少。此外，虽然肾脏疾病是一个影响美国成年人口超过2700万人的公共卫生问题，但人们对肾脏疾病对药物处置的影响知之甚少。本申请的目标是开发一个模型系统，该系统预测人体肾脏的药物排泄，模拟健康和疾病相关的条件。我们建议利用体外3维模块化微生理系统与人肾脏衍生的细胞来鲁棒地模拟人肾脏。微生理学系统将准确反映人体生理学，可用于预测外源性物质的肾脏处理，并将评估内源性和外源性毒物对肾脏损伤的反应。我们还建议与其他研究人员密切合作，以便最终将我们的肾脏模块与 其他器官或组织模块，以实现UH 3阶段的“系统生物学和医学”方法。为了实现这一目标，我们建立了一个多学科的研究团队，拥有肾脏细胞和分子生物学、肾脏毒理学、药代动力学建模、血管生物学和生物医学工程方面的专业知识。这将为UH 2/UH 3联合体创造一个具有巨大效用的独特资源。拟议的研究计划，通过模拟健康和疾病中的肾细胞功能，提高我们对外源性物质排泄决定因素的理解，有可能对公众健康产生巨大影响。