Role and Relevance of Pept1 in Drug Absorption, Disposition, and Dynamics

描述（由申请人提供）：PEPT 1是一种SLC 15家族的质子偶联寡肽转运蛋白（POT），具有营养重要性，因为它可以在肠道内吸收来自饮食的小肽，还可以在肾脏中重吸收来自肾小球滤液的肽结合氨基氮。PEPT 1在其转运治疗剂（例如，?-内酰胺抗生素、血管紧张素转化酶抑制剂、抗病毒核苷前药）和潜在毒性的肽模拟物（例如，5-氨基乙酰丙酸）。然而，POT家族的其他成员（即，PEPT 2、PHT 1和PHT 2）在肠和肾中表达，从而混淆了对其作用和相关性的准确评估。我们的实验室最近建立了一个PEPT 1基因敲除小鼠的群体，这是一个独特的资源，可以通过体内整体动物实验来验证原位机制研究。考虑到最近异常PEPT 1结肠表达与炎症性肠病进展的相关性，这些敲除小鼠的可用性特别令人兴奋。考虑到这一点，本“重新提交”申请的长期目标是确定PEPT 1的生理、药理和病理作用及其相关性。我们的工作假设是PEPT 1是肽和肽样药物在肠道吸收、处置和动力学中的关键转运蛋白，并且它在肠道炎症的发病机制中起重要作用。为了检验这一假设，提出了以下具体目标：目标1。确定肽样药物（和前药）、细菌衍生肽和抗炎三肽的原位肠转运性质;目的2.表征肽样药物（和前药）和抗炎三肽的体内吸收和处置;以及目的3.评价PEPT 1在介导细菌衍生肽和抗炎三肽的炎症反应中的作用和相关性。通过结合野生型和PEPT 1缺失小鼠的细胞/组织、分子和整个动物研究，提出的研究将极大地促进我们对肽、肽样药物（和前药）通过PEPT 1（与其他转运蛋白和/或被动过程相反）的体内作用、意义和载体转运的理解。此外，我们的研究结果将为PEPT 1介导的肠道炎症机制提供重要的新见解，从而为炎症性肠病的治疗策略确定新的靶点。最后，拟议的研究可能会提供罕见的洞察肽/模拟动力学和响应的变异性，在这些人类受试者的遗传多态性。

DESCRIPTION (provided by applicant): PEPT1, a proton-coupled oligopeptide transporter (POT) of the SLC15 family, has nutritional importance because of its intestinal absorption of small peptides from the diet and because of its reabsorption of peptide-bound amino nitrogen from glomerular filtrate in kidney. PEPT1 also has pharmacological significance in its ability to transport therapeutic agents (e.g., ?-lactam antibiotics, angiotensin-converting enzyme inhibitors, antiviral nucleoside prodrugs) and potentially toxic peptidomimetics (e.g., 5-aminolevulinic acid). However, other members of the POT family (i.e., PEPT2, PHT1 and PHT2) are expressed in the intestine and kidney, thereby confounding an accurate assessment of its role and relevance. Our laboratory has recently established a colony of PEPT1 knockout mice, a unique resource in which to validate in situ mechanistic studies with in vivo whole animal experiments. The availability of these knockout mice is particularly exciting given the recent association of aberrant PEPT1 colonic expression and inflammatory bowel disease progression. With this in mind, the long-term objectives of this "resubmission" application are to define the physiological, pharmacological, and pathological roles and relevance of PEPT1. Our working hypothesis is that PEPT1 is a critical transporter in the intestinal absorption, disposition, and dynamics of peptides and peptide-like drugs, and that it plays an important role in the pathogenesis of intestinal inflammation. To test this hypothesis, the following specific aims are proposed: Aim 1. To determine the in situ intestinal transport properties of peptide-like drugs (and prodrugs), bacterially-derived peptides, and anti- inflammatory tripeptides; Aim 2. To characterize the in vivo absorption and disposition of peptide-like drugs (and prodrugs), and anti-inflammatory tripeptides; and Aim 3. To evaluate the role and relevance of PEPT1 in mediating the inflammatory response to bacterially-derived peptides and anti-inflammatory tripeptides. By combining cellular/tissue, molecular, and whole animal studies in wild-type and PEPT1 null mice, the proposed studies will greatly advance our understanding of the in vivo role, significance and vectorial transport of peptides, peptide-like drugs (and prodrugs) by PEPT1 (as opposed to other transporters and/or passive processes). Moreover, our findings will provide important new insights into the mechanisms of PEPT1- mediated intestinal inflammation and, as a result, identify a new target for therapeutic strategies against inflammatory bowel disease. Finally, the proposed studies may offer rare insight into the variability of peptide/mimetic kinetics and response in those human subjects with genetic polymorphisms.