HETEROGENEITY OF RENAL PEPTIDE TRANSPORTERS

专门的转运体，如肾肽转运系统， 在多肽结合的选择性重吸收中发挥重要作用 氨基酸，以及在调节血浆浓度中 小肽。这种独特的交通系统也具有重要的意义 药理相关性，因为它识别β-内酰胺类抗生素 (氨基头孢菌素和氨基青霉素类)，抗癌化合物 血管紧张素转换酶抑制剂(奎那普利)和AS 结果是它们的药代动力学曲线的一个重要决定因素， 毒性和治疗效果。然而，系统的研究涉及 肾肽转运的细胞基础相对较少， 几乎没有关于特定多肽的异质性的信息。 沿肾单位的运输者。这项提案的重点是 哺乳动物肾脏和肾脏中寡肽转运体的特性 特别是，PEPT1和PEPT2这两种异构体的研究 不断壮大的质子偶联多肽转运体家族。我们的具体目标 包括： 目的1.确定多肽转运活性的异质性。 哺乳动物肾脏不同区域刷状缘膜的研究 囊泡和杂交种耗竭研究。 目的：研究肾小管上皮细胞的组织分布和定位。 哺乳动物肾脏中的PEPTI和PEPT2。 目的3.鉴定多肽和多肽的底物专一性。 哺乳动物肾脏中特异性寡肽转运体的类药物 (即PEPT1和PEPT2)在非洲爪哇卵母细胞中表达。 潜在的假设是，对多肽转运体的理解 异质性(即活动、分布-本地化、结构-- 功能)将对肾脏的一般原理提供独特的见解 在功能和分子水平上的肽-质子共转运。 从拟议的实验中收集的知识也将具有 对应用程序的重大影响，甚至对设计的影响 临床重要药物用于治疗感染、癌症、高血压、 充血性心力衰竭和潜在的其他疾病状态。 最终，这些研究将为未来的提案铺平道路。 关于肾脏多肽转运体的调节 生理和病理条件。

Specialized transporters, such as the renal peptide transport system, play a significant role in the selective reabsorption of peptide-bound amino acids as well as in the regulation of plasma concentrations for small peptides. This unique transport system also has significant pharmacological relevance in that it recognizes Beta3-lactam antibiotics (aminocephalosporins and aminopenicillins), anticancer compounds (bestatin), angiotensin-converting enzyme inhibitors (quinapril) and, as a result, is an important determinant of their pharmacokinetic profile, toxicity and therapeutic efficacy. However, systematic studies concerning the cellular basis of renal peptide transport are relatively few and there is almost no information on the heterogeneity of specific peptide transporters along the nephron. This proposal focuses on the characterization of oligopeptide transporters in mammalian kidney and, in particular, the study of PEPT1 and PEPT2, two isoforms in a novel and growing family of proton-coupled peptide transporters. Our specific aims are: Aim 1. to define the heterogeneity of peptide transport activity in different regions of mammalian kidney using brush border membrane vesicles and hybrid depletion studies. Aim 2. to determine the tissue distribution and tubular localization of PEPTI and PEPT2 in mammalian kidney. Aim 3. to characterize the substrate specificity of peptides and peptide- like drugs for specific oligopeptide transporters in mammalian kidney (i.e., PEPT1 and PEPT2) expressed in Xenopus laevis oocytes. The underlying hypothesis is that an understanding of peptide transporter heterogeneity (i.e., activity, distribution-localization, structure- function) will offer unique insights into the general principles of renal peptide-proton cotransport at a functional as well as molecular level. The knowledge gleaned from the proposed experiments will also have significant implications for the application, and perhaps design, of clinically important drugs used to treat infection, cancer, hypertension, congestive heart failure and potentially other disease states. Ultimately, these studies will pave the way for future proposals concerning the regulation of peptide transporters in kidney under physiological and pathological conditions.