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Proximal Tubule Albumin Transport in Disease States.

疾病状态下的近端小管白蛋白转运。

基本信息

批准号：
9309881
负责人：
Bruce A Molitoris
金额：
$ 48.74万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-30 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9309881
关键词：
Affect Albumin Receptors Albumins Albuminuria Amino Acids Animal Model Apical Area Binding Biochemical Biological Assay Calcium Binding Cell Culture Techniques Cell model Cell physiology Cells Cellular Metabolic Process Clinical Clinical Research Data Defect Development Disease Disease Progression Endocytosis Equilibrium Filtration Future Glycoproteins Goals Human Image Imaging Techniques Individual Kidney Knock-in Knock-out LDL-Receptor Related Protein 2 Liquid substance Mediating Metabolism Methods Modeling Modification Molecular Neonatal Pathologic Pathway interactions Phase Physiological Play Post-Translational Protein Processing Process Proteins Proteinuria Proteomics Rattus Reagent Receptor Cell Role Sorting - Cell Movement Surface Techniques Testing Therapeutic Therapeutic Agents Toxic effect Translations Urine apical membrane cell injury clinically relevant fetal glomerular filtration glycation glycosylation imaging approach immunoglobulin receptor in vivo insight intravital imaging intrinsic factor-cobalamin receptor mutant neonatal Fc receptor novel novel therapeutic intervention receptor receptor mediated endocytosis therapeutic target trafficking transcytosis two-photon uptake urinary

项目摘要

Project Summary While the clinical relevance of proteinuria, and especially albuminuria, has been well documented the quantitative mechanistic contribution or role of different contributing components to albuminuria remains an area of considerable excitement . In particular, the role of proximal tubules in albumin reabsorption and reclamation is now known to be an important determinant of the urinary barrier to albuminuria under physiologic and pathologic conditions. Therefore, the present application proposes to dissect apart and quantify the contributions of the known proximal tubule receptors cubilin/megalin and the fetal neonatal immunoglobulin receptor (FcRn) for albumin. To accomplish this we will quantify the interactions of cubilin and FcRn with albumin utilizing a stepwise and synergistic combination of biochemical solution binding assays, cell culture uptake, trafficking and receptor knock out studies in human proximal tubule cells and in vivo kidney studies using Munich Wistar Fromter rats with surface Glomeruli and 2-photon dynamic imaging. Biochemical, structural, functional and mechanistic observations will be interrelated to advance our present understanding of this clinically important phenomenon. Our Overall Hypothesis is that by understanding how albumin interacts with and is affected by these two receptors we will then understand how proximal tubule cells play fundamental, interactive and inducible roles to try and maintain the physiological state and minimize albuminuria. Our ultimate goal is to eventually develop a clinical approach that will allow quantification of the origin of albuminuria as either a proximal tubule or glomerular primary defect or a combination of both. This will allow for more specific therapeutic targets and agents to be identified. To directly evaluate this hypothesis we have developed the necessary techniques, approaches and cell and animal models to dissect, quantify and understand the process of proximal tubule metabolism of albumin.

项目摘要虽然蛋白尿，特别是蛋白尿的临床相关性已经很好，记录了不同贡献的定量机制贡献或作用蛋白尿的成分仍然是一个相当令人兴奋的领域。特别是，作用近端小管在白蛋白重吸收和回收中的作用是一个重要的在生理和病理条件下蛋白尿的尿屏障的决定因素。因此，本申请提出剖析并量化这些因素的贡献。已知的近端小管受体cubilin/megalin和胎儿新生儿免疫球蛋白受体（FcRn）用于白蛋白。为了实现这一点，我们将量化cubilin和FcRn与白蛋白利用生化溶液结合测定的逐步和协同组合，人近端小管细胞的细胞培养物摄取、运输和受体敲除研究，使用慕尼黑Wistar Fromter大鼠进行的体内肾脏研究，具有表面肾小球和2-光子动态成像生物化学，结构，功能和机制的观察将是相互关联，以促进我们目前对这一临床重要现象的理解。我们总的假设是，通过了解白蛋白如何与通过这两种受体，我们将了解近曲小管细胞如何基本的，互动的和诱导的角色，试图维持生理状态，减少蛋白尿我们的最终目标是最终开发出一种临床方法这将允许定量白蛋白尿的起源，无论是近端小管或肾小球原发性缺陷或两者的组合。这将允许更具体的待鉴定的治疗靶点和药剂。为了直接评估这个假设，我们有开发了必要的技术，方法和细胞和动物模型来解剖，量化和了解近端小管代谢白蛋白的过程。