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.

抽象的 慢性肾脏疾病（CKD）定义为肾脏损伤或肾小球过滤率的降低三个 几个月或更长时间，无论原因如何。 CKD影响全球约2.76亿人，导致减少 生活质量，发病率，死亡率和医疗保健成本提高。对于许多人来说，CKD发展到最终阶段 肾脏疾病（ESRD）以及透析和移植的需求。蛋白质异常泄漏到尿液中（即 蛋白尿症与较差的预后和更大的ESRD进展可能性有关。尽管 通常将蛋白尿疾病研究为肾小球和居民足细胞的疾病，我们建议 肾脏块茎也可能在促进肾小球蛋白尿中起关键作用。 β-catenin是转录因子 肾脏受伤期间活跃于块茎上皮。初步数据表明，管特异性β-catenin敲除 小鼠免受肾小球损伤和蛋白尿的保护，表明小鼠可以在肾小球中起作用 疾病。该保护与单核细胞趋化剂蛋白1的表达降低有关（MCP- 1），并且已知MCP-1会对肾小球的居民足细胞产生不利影响。因此，我们假设 响应损伤的肾小管到胶质性串扰涉及β-catenin介导的MCP-1释放 肾小管。该假设将通过三个目标进行检验。首先，我们将研究β-catenin的作用 在肾管中诱导的MCP-1表达上。其次，我们将评估MCP-1对缝隙隔膜的影响 正直。第三，我们将研究管特异性MCP-1在肾小球发展中的贡献 损伤和足细胞功能障碍。该建议将为邦迪博士提供更多的机会 具有肾脏损伤模型的经验，建立有条件的遗传基因敲除鼠标模型，肾脏 来自芯片和芯片序列实验的成像，执行和分析数据，并保持 分子技术的快速技术进步。邦迪博士将亲自与 由成熟和经验丰富和经验丰富的导师，顾问和合作者的团队指导，以确保成功 提案完成。通过获得K01的支持，邦迪博士将能够利用核心 匹兹堡大学内外提供的资源，讲习班和课程。邦迪·威尔博士 使用此建议来实现获得其他技术和专业培训的短期目标， 以及成为肾脏疾病中领先的主要研究员的长期目标，并获得了全资金 维持生产力，促进合作并提供指导的实验室。总体而言，结果 从该提案中，不仅将构成R01研究的基础，而且会导致对CKD和 提供重要的机械数据，这对于开发未来治疗干预措施至关重要 蛋白酶CKD。