Engineering Proteins for Reabsorption in the Renal Proximal Tubule

1264807 Lazzara，Matthew J.肾脏从血浆中清除蛋白质是导致蛋白质类治疗剂生物利用度降低的最重要途径之一。对于不能被肾小球毛细血管壁的过滤装置有效地保留并且不能从近端小管内的初级尿中有效地重吸收的蛋白质，这种蛋白质通过肾系统的损失最大。虽然一些基于蛋白质的治疗剂已经通过共价修饰或与大体积惰性蛋白质融合而被工程化以降低肾清除率，但此类修饰可能改变对预期靶组织的治疗可用性。研究人员建议确定白蛋白内的最小表位，这些表位通过近端上皮中表达的同源转运受体触发这种丰富的血浆蛋白的有效近端小管重吸收，并使用这些信息来设计可以与任何治疗蛋白融合的通用肽，以通过引起其完整的重吸收来降低其肾清除率。实验目标将利用研究人员内部的工具？这些实验室可以设计蛋白质，分析蛋白质与细胞和受体的相互作用，并测量细胞内蛋白质运输过程。计算目标将利用质量传输和动力学建模方法来创建一个定量框架，用于预测蛋白质结合和内吞作用的变化如何提高治疗生物利用度以及如何优化蛋白质工程。此外，本项目还将通过综合教育项目产生更广泛的影响，在这些项目中，研究目标背后的科学将在多个教育环境中传播给学生和教师。基于蛋白质的治疗由于其精致的生物功能和特异性而变得越来越普遍。调查员？这项工作将对增强治疗性蛋白质功效具有广泛的意义。事实上，模型蛋白质完整重吸收的成功工程将使该技术能够应用于任何基于蛋白质的治疗，并为基于蛋白质的药物创造一种全新的模块化。这具有通过增强治疗功效和患者治疗方案以及减少与基于蛋白质的药物的生产和施用相关的经济负担而产生巨大社会影响的潜力。

1264807Lazzara, Matthew J. The clearance of proteins from plasma by the kidneys constitutes one of the most significant pathways leading to reduced bioavailability of protein-based therapeutics. The loss of such proteins via the renal system is greatest for proteins which are not efficiently retained by the filtration apparatus of the glomerular capillary wall and which are not efficiently reabsorbed from the primary urine within the proximal tubule. While some protein-based therapeutics have been engineered for reduced renal clearance by covalent modification or fusion to bulky inert proteins, such modifications may alter therapeutic availability to intended target tissues. The investigators propose to identify minimal epitopes within albumin that trigger the efficient proximal tubule reabsorption of this abundant plasma protein through cognate transport receptors expressed in the proximal epithelium and to use this information to engineer generic peptides that can be fused to any therapeutic protein to reduce its renal clearance by causing its intact reabsorption. The experimental aims will leverage tools within the investigators? laboratories to engineer proteins, analyze protein interactions with cells and receptors, and measure intracellular protein trafficking processes. The computational aim will leverage mass transport and kinetic modeling approaches to create a quantitative framework for predicting how changes to protein binding and endocytosis will improve therapeutic bioavailability and how to optimally engineer proteins. In addition, this project will have broader impact through integrated educational programs in which the science behind the research objectives will be disseminated to students and teachers in multiple educational settings.Protein-based therapeutics are becoming increasingly common due to their exquisite biological functions and specificities. The investigators? work will have broad implications for enhancing therapeutic protein efficacy. Indeed, the successful engineering of the intact reabsorption of model proteins will enable the application of this technology to any protein-based therapeutic and create a fundamentally new modularity for protein-based drugs. This has potential for tremendous societal impact through enhancement of therapeutic efficacy and patient treatment regimens, as well as reduction in the financial burden associated with production and administration of protein-based drugs.