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.

项目概要 随着慢性肾脏病的增加，我们必须找出更好的治疗策略来避免 医疗保健危机。目前的治疗干预措施解决的是患者的症状而不是根本原因 从而不会显着减缓疾病进展。开发药物来治疗根本原因或 导致 CKD 的疾病将满足这一需求，但这种进展因缺乏 用于药物开发管道的体外人类肾脏模型。因此，体外模型可以准确地 模拟个体人类 CKD 并可筛选与疾病相关的治疗干预措施是当务之急 需要确定有针对性的 CKD 干预措施。第二阶段 SBIR 是第一阶段成功的延续， 这是 MIMETAS 和洛杉矶儿童医院 (CHLA) 的合作成果。我们将一起 专注于满足药物中使用的 3D 肾脏芯片平台（称为 NephroPlate）的市场需求 发现。 NephroPlate 将能够评估肾功能对循环和遗传的反应 CKD 致病因素。对于这个第二阶段项目，我们将重点关注肾小球疾病 以前的经验，阿尔波特综合征和膜性肾病，以及哪里有很高的需求 NephroPlate 客户、糖尿病肾病和 APOL1 肾病。对于每个 CKD，我们将描述 通过测量通道来确定表型（免疫染色、蛋白质印迹、RNAseq）和肾小球滤过功能 微流体系统内的荧光白蛋白和跨上皮电阻（TEER）。全部 系统将根据高通量药物筛选标准进行验证。肾小球芯片滤液 培养物将被转移到近端小管芯片培养物中，以评估肾小球疾病的影响 近端小管上。最后，将对肾小球和近端小管滤液进行蛋白质组学分析，以鉴定 每种 CKD 特有的潜在生物标志物。一旦执行，这些研究将确立肾板作为 高通量药物筛选平台，供制药公司和学术实验室使用 研究 CKD 疾病的机制并最终确定疾病特异性治疗方法。