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 慢性肾脏病（CKD）定义为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影响着全球约2.76亿人，导致 生活质量下降，发病率、死亡率和医疗费用增加。对于许多人来说，CKD进展到终末期 肾脏疾病（ESRD）和需要透析和移植。蛋白质异常渗漏到尿液中（即， 蛋白尿）与更差的预后和更大的进展为ESRD的可能性相关。而 蛋白尿性疾病通常被研究为肾小球和常驻足细胞的疾病，我们提出， 肾小管也可能在促进肾小球蛋白尿中起关键作用。β-连环蛋白是一种转录因子 在肾损伤时在肾小管上皮细胞中有活性。初步数据显示，小管特异性β-连环蛋白敲除 保护小鼠免于肾小球损伤和蛋白尿，这表明肾小管在肾小球损伤中起作用。 疾病这种保护作用与单核细胞趋化蛋白-1（MCP-1）的表达减少有关。 1），并且已知MCP-1不利地影响肾小球的常驻足细胞。因此，我们假设 损伤时肾小管-肾小球间的相互作用涉及β-连环蛋白介导的MCP-1的释放， 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-catenin在 对诱导肾小管中MCP-1表达的影响。其次，我们将评估MCP-1对狭缝光阑的影响 完整第三，我们将研究肾小管特异性MCP-1在肾小球疾病发生中的作用。 损伤和足细胞功能障碍。这一提议将为邦迪博士提供获得额外资金的机会。 啮齿动物肾损伤模型的经验，条件性基因敲除小鼠模型的建立，肾 成像，执行和分析来自ChIP和ChIP-seq实验的数据，以及了解 分子技术的快速发展。邦迪博士将亲自与之互动并成为 由一个有成就和经验丰富的导师，顾问和合作者团队指导，以确保成功 完成提案。有了K 01的支持，Bondi博士将能够利用核心 资源，研讨会和匹兹堡大学内外提供的课程。邦迪博士将 利用这一建议来实现获得额外技术和专业培训的短期目标， 和长期目标，成为一个领先的初级肾脏疾病教育工作者， 实验室，保持生产力，促进合作，并提供指导。总的来说，结果 这一建议不仅将成为R 01研究的基础，而且将导致对CKD的新理解， 提供了重要的机制数据，这对未来治疗干预的发展至关重要， 蛋白尿性CKD。