Juxta-glomerular cells serve as glomerular epithelial cell progenitors in glomerular disease

肾小球旁细胞在肾小球疾病中充当肾小球上皮细胞祖细胞

• 批准号: 9816246
• 负责人: Stuart James Shankland
• 金额: $ 62.07万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-05 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9816246
• 关键词: Acute; Address; Adult; Aging; Agonist; Angiotensin Receptor; Angiotensin-Converting Enzyme Inhibitors; Animals; Biological Assay; Biology; Biomedical Engineering; Cell Culture Techniques; Cell Line; Cell Lineage; Cells; Chronic; Chronic Kidney Failure; Cicatrix; Complex; Cultured Cells; Data; Data Analyses; Development; Devices; Dialysis procedure; Dimensions; Disease; End stage renal failure; Endocrine; Epithelial; Epithelial Cells; Equilibrium; Fibrosis; Focal Segmental Glomerulosclerosis; Functional disorder; Goals; Grant; In Vitro; Injury; Juxtaglomerular Cell; Kidney; Kidney Transplantation; Knowledge; Label; Lead; Link; Logic; Maintenance; Mesenchymal; Methodology; Methods; Molecular; Mus; Natural regeneration; Outcome; Parietal; Pathway interactions; Pericytes; Phenotype; Proliferating; Proteins; Public Health; Ramp; Regulation; Renal glomerular disease; Renin; Reporter; Reporting; Research; Role; Signal Pathway; Signal Transduction; Source; Stem cells; System; Testing; Therapeutic; Transgenic Mice; Tubular formation; WNT Signaling Pathway; WT1 gene; base; beta catenin; cell type; design; drug development; experimental study; functional restoration; genetic approach; improved; in vivo; innovation; kidney cell; mesangial cell; migration; mouse model; novel; novel therapeutics; pluripotency; podocyte; prevent; progenitor; self-renewal; stem; stemness; theories; transcription factor; transcriptomics; transdifferentiation

PROJECT SUMMARY Chronic kidney disease (CKD) is increasing in the US, now impacting at least one in ten people. CKD typically results in end-stage kidney disease (ESRD), that requires either dialysis or kidney transplantation. Proteinuric glomerular diseases are the major cause of CKD and ESRD and are generally caused by progressive podocyte loss followed by glomerular scarring. Because podocytes are terminally differentiated epithelial cells they cannot regenerate. Therefore, following loss in disease, partial or complete podocyte replacement relies on trans-differentiation of adjacent progenitor cells. These include parietal epithelial cells, and cells of the renin lineage (CoRL), the latter being the focus of this competitive renewal. Unfortunately, endogenous podocyte replacement is often not robust enough to assure protection. Given this situation, and to address the unmet need to augment podocyte replacement through discovery of new targets, our long-term goal is to understand the mechanisms underlying podocyte regeneration, and identify therapeutic options towards restoring podocyte numbers and preventing glomerular scaring. We recently reported that CoRL are pluri-potent progenitors that can trans-differentiate towards podocytes, parietal epithelial cells, mesengial cells and pericytes. We have also shown that the transcription factor Wt1 is a critical player and is necessary for CoRL proliferation and migration, and its trans-differentiation to a podocyte fate. However, the precise molecular mechanism(s) underlying this CoRL biology are still poorly understood. To resolve this, the overall objective of this application is to investigate the mechanisms and pathways to augment CoRL progenitor function and its trans- differentiation into podocytes. Our central hypothesis is that we can ramp up the ability of these CoRL to become podocytes, and replace those lost by modulating distinct signaling systems such as Wnt signaling. To test this, we will pursue two Specific Aims: (1) Test the hypothesis that the progenitor capacity of cells of renin lineage (CoRL) to trans-differentiate to a podocyte fate is governed by the balance of WT1 and Wnt signaling, and (2) Identify pathways underlying the pluripotency of cells of renin lineage towards different adult kidney cell type fates in glomerular diseases. The approach is innovative as it is based on a unique ability to culture CoRL ex vivo, innovative bioengineered cell culture devices, a newly developed dual-reporter mice to definitively trace CoRL-podocyte trans-differentiation, and Quality-by-Design (QbD)-based methodologies to identify complex and robust culture conditions. The research is significant as it provides an in depth understanding of the potential of CoRL to differentiate into multiple kidney cell types even in adults. In addition, it will advance the field by identifying potentially novel therapeutic options towards restoring podocyte numbers, and in doing so, preventing and even reversing glomerular scaring in proteinuric glomerular diseases.

项目总结 慢性肾脏疾病(CKD)在美国正在增加，目前至少有十分之一的人受到影响。CKD通常 导致终末期肾病(ESRD)，需要透析或肾移植。蛋白尿酸 肾小球疾病是慢性肾脏病和终末期肾病的主要原因，通常由进行性肾小球疾病引起 足细胞丢失，肾小球瘢痕形成。因为足细胞是终末分化的上皮细胞 它们不能再生。因此，在疾病丧失后，部分或全部足细胞替换依赖于 关于相邻祖细胞的转分化。这些细胞包括壁上皮细胞和肾素细胞。 血统(科尔)，后者是这次竞争更新的焦点。不幸的是，内源性足细胞 替代往往不够坚固，不足以确保保护。在这种情况下，并解决未满足的问题 需要通过发现新的靶点来增加足细胞的替换，我们的长期目标是了解 足细胞再生的潜在机制，并确定修复足细胞的治疗方案 数字和防止肾小球惊吓。我们最近报道COIL是多能祖细胞， 可以向足细胞、壁上皮细胞、系膜细胞和周细胞跨向分化。我们还有 研究表明，转录因子Wt1是COIL增殖和生长所必需的关键因子。 迁徙及其转分化为足细胞的命运。然而，精确的分子机制(S) 在这种情况下，科尔的生物学仍然知之甚少。为了解决这个问题，本应用程序的总体目标是 目的是探讨增强COIL祖细胞功能及其反式作用的机制和途径。 分化为足细胞。我们的中心假设是，我们可以增强这些细胞的能力 成为足细胞，并通过调制不同的信号系统(如WNT信号)来取代丢失的足细胞。至 检验这一点，我们将追求两个具体目标：(1)检验肾素祖细胞能力的假说 转分化为足细胞命运的谱系(COIL)受WT1和Wnt信号平衡的控制， 以及(2)确定肾素谱系细胞对不同成人肾脏细胞的多能性的潜在途径 肾小球疾病的分型命运。这种方法是创新的，因为它基于培养Corl的独特能力 体外，创新的生物工程细胞培养设备，新开发的双报告小鼠最终确定 跟踪足细胞转分化和基于设计质量(QBD)的方法，以确定 复杂而稳健的培养条件。这项研究具有重要意义，因为它提供了对 COIL分化为多种肾细胞类型的潜力，即使在成人。此外，它还将推进 通过确定潜在的新的治疗方案来恢复足细胞数量，并在 因此，预防甚至逆转蛋白尿性肾小球疾病的肾小球瘢痕。