The Role of MCP-1 in Tubular-to-Glomerular Crosstalk in Proteinuric Kidney Disease

MCP-1 在蛋白尿肾病肾小管与肾小球串扰中的作用

• 批准号: 10452674
• 负责人: Corry Dominic Bondi
• 金额: $ 14.77万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-16 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10452674
• 关键词: Ablation; Adriamycin PFS; Affect; Albumins; Angiotensin II; Automobile Driving; Binding; Biology; CCL2 gene; Cell Culture Techniques; Cells; Chronic Kidney Failure; Collaborations; Data; Data Analyses; Development; Dialysis procedure; Disease; Disease Progression; Down-Regulation; Educational workshop; End stage renal failure; Ensure; Enzyme-Linked Immunosorbent Assay; Epithelial; Epithelial Cells; Excretory function; Exposure to; Extravasation; Filtration; Foot Process; Fostering; Functional disorder; Funding; Future; Genetic; Glomerular Filtration Rate; Goals; Health; Health Care Costs; Immunofluorescence Immunologic; In Vitro; Injury; Injury to Kidney; Kidney; Kidney Diseases; Kidney Failure; Knockout Mice; Laboratories; Mediating; Mentored Research Scientist Development Award; Mentors; Mentorship; Messenger RNA; Modeling; Molecular; Morbidity - disease rate; Morphology; Mus; Nephrons; Pathway interactions; Permeability; Persons; Plasma; Play; Production; Productivity; Prognosis; Proteins; Proteinuria; Quality of life; Rattus; Receptor Activation; Renal function; Renal glomerular disease; Renal tubule structure; Research; Research Personnel; Resources; Rodent Model; Role; Route; Serum Proteins; Small Interfering RNA; Structure; Technology; Testing; Therapeutic Intervention; Time; Training; Transmission Electron Microscopy; Transplantation; Travel; Tubular formation; Universities; Urine; Writing; beta catenin; chromatin immunoprecipitation; cofactor; experience; experimental study; glomerulosclerosis; in vivo; inhibitor; kidney imaging; monocyte chemoattractant protein 1 receptor; mortality; mouse model; neglect; neutralizing antibody; novel; podocyte; promoter; protein expression; renal damage; response; response to injury; slit diaphragm; transcription factor; urinary

ABSTRACT Chronic kidney disease (CKD) is defined as kidney damage or reduction in glomerular filtration rate for three months or more, irrespective of cause. CKD affects an estimated 276 million people worldwide, leads to reduced quality of life and increased morbidity, mortality, and healthcare costs. For many, CKD progresses to end-stage renal disease (ESRD) and the need for dialysis and transplantation. Abnormal leak of protein into the urine (i.e., proteinuria) is associated with a worse prognosis and greater likelihood of progression to ESRD. While proteinuric diseases are generally studied as a disease of the glomeruli and resident podocytes, we propose that the renal tubules may also play a key role in promoting glomerular proteinuria. β-catenin is a transcription factor active in tubular epithelia during kidney injury. Preliminary data show that tubule-specific β-catenin knockout mice are protected from glomerular injury and proteinuria, suggesting that tubules can play a role in glomerular disease. This protection was associated with reduced expression of monocyte chemoattractant protein-1 (MCP- 1), and MCP-1 is known to adversely affect the resident podocytes of the glomerulus. Therefore, we hypothesize that tubular-to-glomerular crosstalk in response to injury involves the β-catenin-mediated release of MCP-1 from kidney tubules. This hypothesis will be tested through three aims. First, we will investigate the effect of β-catenin on inducing MCP-1 expression in renal tubules. Second, we will assess the effect of MCP-1 on slit diaphragm integrity. Third, we will investigate the contribution of tubule-specific MCP-1 in the development of glomerular injury and podocyte dysfunction. This proposal will provide Dr. Bondi with the opportunity to acquire additional experience with rodent models of kidney injury, establishing conditional genetic knockout mouse models, kidney imaging, performing and analyzing data from both ChIP and ChIP-seq experiments as well as staying abreast of the rapid, technological advances in molecular technologies. Dr. Bondi will personally interact with and be mentored by a team of accomplished and experienced mentors, advisors, and collaborators to ensure successful completion of the proposal. By having the K01 support, Dr. Bondi will be able to take advantage of core resources, workshops, and courses offered within and outside of the University of Pittsburgh. Dr. Bondi will use this proposal to accomplish the short-term goal of acquiring additional technical and professional training, and the long-term goal of becoming a leading primary investigator-educator in kidney disease with a fully-funded laboratory, which maintains productivity, fosters collaborations, and provides mentorship. Overall, the results from this proposal will not only form the basis for a R01 study but will lead to a new understanding of CKD and provide important mechanistic data that is critical for the development of future therapeutic interventions for proteinuric CKD.

摘要 慢性肾脏病(CKD)的定义是肾损害或肾小球滤过率降低 几个月或更长时间，无论原因如何。CKD影响全球约2.76亿人，导致 生活质量和增加的发病率、死亡率和医疗费用。对许多人来说，CKD进展到了末期 肾脏疾病(终末期肾病)以及透析和移植的需要。蛋白质异常泄漏到尿液中(即， 蛋白尿)与预后更差和进展为终末期肾病的可能性更大有关。而当 蛋白尿性疾病通常被研究为肾小球和足细胞的疾病，我们建议 肾小管也可能在促进肾小球蛋白尿方面发挥关键作用。β-连环蛋白是一种转录因子 肾损伤时活跃于肾小管上皮细胞。初步数据显示，小管特异的β-连环蛋白基因敲除 小鼠不受肾小球损伤和蛋白尿的影响，这表明小管在肾小球中可以发挥作用。 疾病。这种保护作用与单核细胞趋化蛋白-1(MCP-1)表达减少有关。 1)，并且已知MCP-1对肾小球驻留的足细胞有不利影响。因此，我们假设 损伤后肾小管至肾小球的串扰与β-连环蛋白介导的单核细胞趋化蛋白-1的释放有关。 肾小管。这一假设将通过三个目标进行检验。首先，我们将研究β-连锁素的作用 诱导肾小管单核细胞趋化蛋白-1的表达。其次，我们将评估MCP-1对缝隙横隔膜的影响 正直。第三，我们将研究小管特异性单核细胞趋化蛋白-1在肾小球发育中的作用。 损伤和足细胞功能障碍。这项提议将为邦迪博士提供机会，获得更多 利用啮齿动物肾脏损伤模型建立条件基因敲除小鼠肾脏模型 对芯片和芯片序列实验的数据进行成像、执行和分析，并与 分子技术的快速技术进步。邦迪博士将亲自与 由一群有成就和经验的导师、顾问和合作者组成的团队指导，确保成功 完成建议书。通过K01的支持，Bondi博士将能够利用CORE 匹兹堡大学内外提供的资源、研讨会和课程。邦迪博士将 利用这一建议实现获得更多技术和专业培训的短期目标， 长期目标是成为肾脏疾病领域领先的初级研究人员和教育工作者，并拥有全额资金 实验室，它保持生产力，促进合作，并提供指导。总体而言，结果 这一建议不仅将构成R01研究的基础，而且将导致对CKD和 提供重要的机制数据，这些数据对于开发未来的治疗干预措施至关重要 蛋白尿型慢性肾脏病。