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: 10612028
• 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/10612028
• 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; Development; Dialysis procedure; Disease; Disease Progression; Down-Regulation; Educational workshop; End stage renal failure; Ensure; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Epithelium; 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; Western Blotting; Writing; beta catenin; chromatin immunoprecipitation; cofactor; experience; experimental study; glomerulosclerosis; in vivo; inhibitor; kidney cortex; 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