Development of the NephroPlate: A high-throughput kidney-on-a-chip platform for identifying chronic kidney disease therapies

NephroPlate 的开发：用于识别慢性肾病治疗的高通量肾芯片平台

• 批准号: 10686105
• 负责人: Kristin M Bircsak
• 金额: $ 99.31万
• 依托单位: MIMETAS US, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-28 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10686105
• 关键词: 3-Dimensional; APOL1 gene; Address; Albumins; Amniotic Fluid; Biological Assay; Biological Markers; Black Populations; Cells; Chronic Kidney Failure; Data; Data Set; Detection; Development; Diabetic Nephropathy; Disease; Disease Progression; Disease model; Drug Modelings; Drug Screening; Electrical Resistance; End stage renal failure; Endothelial Cells; Ensure; Epithelium; Evaluation; Exhibits; Exposure to; Filtration; Fluorescein-5-isothiocyanate; Gene Expression; Genetic; Health; Healthcare; Hereditary nephritis; Hormones; Human; In Vitro; Individual; Inherited; Injury; Injury to Kidney; Intervention; Kidney; Kidney Diseases; Laboratories; Los Angeles; Marketing; Measures; Mediating; Membranous Glomerulonephritis; Microfluidics; Modeling; Mutation; Outcome; Patients; Pediatric Hospitals; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phenotype; Physiological; Population; Process; Proteomics; Reading; Regulation; Renal function; Renal glomerular disease; Reporting; Reproducibility; Serum; Small Business Innovation Research Grant; Structure; Symptoms; System; Therapeutic; Therapeutic Intervention; Tissue Model; Tubular formation; United States; Western Blotting; biomarker discovery; biomarker identification; drug candidate; drug development; drug discovery; efficacy study; epithelial to mesenchymal transition; experience; glomerular basement membrane; glomerular endothelium; glomerular filtration; high throughput screening; high-throughput drug screening; improved; in vitro Model; novel; novel therapeutics; organ on a chip; patient population; podocyte; potential biomarker; prevent; racial health disparity; response; risk variant; screening; specific biomarkers; targeted treatment; transcriptome sequencing; treatment strategy

Project Summary With chronic kidney disease on the rise, it is imperative that we identify better treatment strategies to avoid a healthcare crisis. Current therapeutic interventions address patient symptoms rather than the underly cause and thereby do not substantially slow disease advancement. Developing drugs to treat the underlying cause or disorder leading to CKD will address this need, however such advancements have been hampered by the lack of in vitro human kidney models used in the drug development pipeline. Thus, an in vitro model which accurately mimics individual human CKDs and can be screened for disease-relevant therapeutic interventions is urgently needed to identify targeted CKD interventions. This Phase II SBIR is a continuation of a successful Phase I and a collaborative effort between MIMETAS and the Children’s Hospital of Los Angeles (CHLA). Together we will focus on addressing the market need for a 3D kidney-on-a-chip platform, called the NephroPlate for use in drug discovery. The NephroPlate will enable the evaluation of kidney function in response to circulating and genetic factors of CKD-causing disorders. For this Phase II project, we will focus on glomerulopathies where we have previous experience, Alport syndrome and membranous nephropathy, and where there is a high demand from NephroPlate customers, diabetic nephropathy and APOL1 nephropathy. For each CKD, we will characterize phenotype (immunostaining, western blot, RNAseq) and glomerular filtration function by measuring the passage of fluorescent albumin and the trans-epithelial electrical resistance (TEER) within the microfluidic system. All systems will be validated to high-throughput drug screening standards. Filtrate from the glomerulus-on-a-chip cultures will be transferred to the proximal tubule-on-a-chip cultures to evaluate the impact of glomerular disease on proximal tubules. Finally, proteomics will be performed on the glomerular and proximal tubule filtrate to identify potential biomarkers specific to each CKD. Once executed these studies will establish the NephroPlate as a high-throughput drug screening platform for use by pharmaceutical companies and academic laboratories to investigate mechanisms of CKD diseases and ultimately identify disease-specific therapeutics.

项目摘要 随着慢性肾脏疾病的增长，我们必须确定更好的治疗策略以避免 医疗危机。当前的治疗干预措施解决了患者症状，而不是根本原因和 因此，疾病的进步不会大大减缓。开发药物来治疗根本原因或 导致CKD的疾病将满足这种需求，但是由于缺乏，这种进步受到了阻碍 在药物开发管道中使用的体外人类肾脏模型。这是一个准确的体外模型 模仿人类CKD，可以筛查与疾病相关的治疗干预措施 需要确定目标的CKD干预措施。该第二阶段SBIR是成功的I阶段的延续 Mimetas与洛杉矶儿童医院（CHLA）之间的合作努力。我们会在一起 专注于满足市场对3D肾脏平台的需求，该平台称为肾板酸盐用于药物 发现。肾镀以响应循环和遗传的肾脏功能的评估 引起CKD引起的疾病的因素。对于此第二阶段项目，我们将专注于我们拥有的肾小球疾病 以前的经验，Alport综合征和膜性肾病，以及对 肾镀膜客户，糖尿病性肾病和APOL1肾病。对于每个CKD，我们都会描述 表型（免疫染色，蛋白质印迹，RNASEQ）和肾小球过滤功能通过测量密码 微流体系统中的荧光白蛋白和反上皮电阻（TEER）。全部 系统将被验证为高通量药物筛查标准。从芯片上的肾小球上填充物 培养物将被转移到芯片上的近端管培养物，以评估肾小球疾病的影响 在近端管上。最后，将在肾小球和近端细胞滤波器上进行蛋白质组学以识别 每个CKD的潜在生物标志物。执行后，这些研究将确定肾镀酸盐 用于制药公司和学术实验室使用的高通量药物筛查平台 研究CKD疾病的机制，并最终确定疾病特异性疗法。