Kidney Microphysiological Analysis Platforms (MAP) to Optimize Function and Model Disease

用于优化功能和疾病模型的肾脏微生理分析平台 (MAP)

• 批准号: 10226203
• 负责人: JOSEPH VINCENT BONVENTRE
• 金额: $ 100.61万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10226203
• 关键词: 3-Dimensional; 3D Print; Acute; Acute Disease; Adult; Affect; Alleles; Apoptosis; Architecture; Basement membrane; Biocompatible Materials; Biological; Biology; Blood Vessels; CRISPR/Cas technology; Cell Communication; Cell Cycle; Cells; Cellular Structures; Characteristics; Chronic Disease; Chronic Kidney Failure; Clinical Sciences; Clustered Regularly Interspaced Short Palindromic Repeats; Cyst; Cystic Kidney Diseases; Cystic kidney; Cytoskeleton; Development; Devices; Disease; Disease model; Distal; Drug toxicity; Electroencephalography; Endothelial Cells; Endothelium; Engineering; Epithelial; Epithelial Cells; Epithelial Physiology; Extracellular Matrix; Genetic; Genetic Diseases; Genetic Models; Growth Factor; Human; Image; In Vitro; Individual; Induced Mutation; Injury; Kidney; Kidney Diseases; Laboratories; Mendelian disorder; Microfabrication; Microfluidics; Modeling; Monitor; Mutation; Organoids; Patients; Perfusion; Pericytes; Pharmaceutical Preparations; Physiologic Monitoring; Physiological; Population; Prevalence; Preventive; Process; Property; Renal glomerular disease; Reporter; Reproducibility; Research Personnel; Side; Signal Transduction; Structure; System; Techniques; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Toxic effect; Toxicity Tests; Tubular formation; Work; bioprinting; cost; design; design and construction; differentiation protocol; disease phenotype; drug development; drug discovery; drug efficacy; drug testing; efficacy testing; experience; genome editing; glomerular basement membrane; human pluripotent stem cell; human tissue; induced pluripotent stem cell; innovation; kidney cell; kidney vascular structure; microphysiology system; mutant; nephron progenitor; nephrotoxicity; new technology; non-genetic; novel; organ on a chip; planar cell polarity; podocyte; prevent; programs; response; screening; stem cell biology; stem cells; uptake; vector

Project Summary Approximately 10% of the world's adult population has chronic kidney disease (CKD) for which there are very few effective preventive or stabilizing therapeutic options. In addition, 30% of newly developed drugs are not advanced because of nephrotoxicity. We have developed efficient directed differentiation protocols to generate nephron progenitor cells (NPCs) and 3D kidney organoids from human pluripotent stem cells (hPSCs). At present, however, there are no effective platforms that integrate these kidney cells and vascularized organoids within microphysiological systems in vitro to develop effective kidney models for interrogation of nephrotoxicity and drug efficacy. Our proposal unites expertise in kidney organoids and disease, microphysiological systems, and bioprinting led by three experienced investigators (Bonventre, Lee and Lewis) in a unique effort to create these needed model platforms. In Specific Aim 1 we will develop efficient processes to direct differentiation of hiPSCs into kidney podocytes, tubular epithelial cells, and endothelial cells endowed with differentiated features for integration into microphysiological analysis platforms (MAP) and bioprinted structures. We create genetic models of disease and reporter lines that signal differentiation characteristics to optimize differentiation protocols and to monitor physiological parameters. In Specific Aim 2 we will design, construct, and characterize an integrated kidney MAP to evaluate the function of hPSC-derived kidney podocytes, endothelial and epithelial cells as well as kidney organoids. We will also use this platform to create a model of a glomerulus that will have differentiated podocytes on an extracellular matrix (to mimic the glomerular basement membrane) and hiPSC-derived endothelial cells on the other side of the basement membrane. The MAP will be optimized to interrogate basic kidney biology and pathobiology of both non-genetic and genetic disease involving kidney cysts or podocyte injury and test responses to putative therapeutic agents. In Specific Aim 3 we will bioprint a 3D kidney model that contains convoluted proximal tubules, pericytes and endothelial-lined vascular structures with controlled, physiologically relevant system. Modeled tubules and vasculature will be perfused through a open lumens. The ECM composition will be optimized to support confluent epithelialization using proximal and distal tubule cells, podocytes, and endothelial cells derived from hiPSCs. We will characterize polarized drug uptake, toxicity, and vectorial transport through the interstitium (ECM) as well as cell-cell interactions among the epithelial cells, interstitium and endothelium-lined channels to create and validate vascularized kidney models composed of cells derived from healthy and patients with cystic disease that affects the tubule and glomerular disease that affects the podocyte. Our program, with well-established milestones, will result in novel models to test kidney toxicity and drug efficacy.

项目总结

项目成果

Bioengineered Kidney Models: Methods and Functional Assessments.

• DOI: 10.1093/function/zqab026
• 发表时间: 2021
• 期刊: Function (Oxford, England)
• 作者: Rizki-Safitri A;Traitteur T;Morizane R
• 通讯作者: Morizane R

Nephrotoxicity Assessment with Human Kidney Tubuloids using Spherical Nucleic Acid-Based mRNA Nanoflares.

• DOI: 10.1021/acs.nanolett.1c01840
• 发表时间: 2021-07-14
• 期刊: NANO LETTERS
• 影响因子: 10.8
• 作者: Wiraja, Christian;Mori, Yutaro;Ichimura, Takaharu;Hwang, Jangsun;Xu, Chenjie;Bonventre, Joseph, V
• 通讯作者: Bonventre, Joseph, V

3D proximal tubule-on-chip model derived from kidney organoids with improved drug uptake.

• DOI: 10.1038/s41598-022-19293-3
• 发表时间: 2022-09-02
• 期刊: SCIENTIFIC REPORTS
• 影响因子: 4.6
• 作者: Aceves, Jeffrey O.;Heja, Szilvia;Kobayashi, Kenichi;Robinson, Sanlin S.;Miyoshi, Tomoya;Matsumoto, Takuya;Schaffers, Olivier J. M.;Morizane, Ryuji;Lewis, Jennifer A.
• 通讯作者: Lewis, Jennifer A.

Energy depletion by cell proliferation sensitizes the kidney epithelial cells to injury.

细胞增殖造成的能量消耗使肾上皮细胞对损伤敏感。

• DOI: 10.1152/ajprenal.00023.2023
• 发表时间: 2024
• 期刊: American journal of physiology. Renal physiology
• 作者: Galichon,Pierre;Lannoy,Morgane;Li,Li;Serre,Justine;Vandermeersch,Sophie;Legouis,David;Valerius,MTodd;Hadchouel,Juliette;Bonventre,JosephV
• 通讯作者: Bonventre,JosephV

Acute kidney injury and maladaptive tubular repair leading to renal fibrosis.

• DOI: 10.1097/mnh.0000000000000605
• 发表时间: 2020-03
• 期刊: Current Opinion in Nephrology & Hypertension
• 影响因子: 3.2
• 作者: Samuel Mon-Wei Yu;J. Bonventre