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

Pept1 在药物吸收、处置和动力学中的作用和相关性

基本信息

批准号：
8470169
负责人：
DAVID E SMITH
金额：
$ 32.53万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
1988
资助国家：
美国
起止时间：
1988-02-01 至 2014-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8470169
关键词：
Accounting Affect Aminolevulinic Acid Angiotensin-Converting Enzyme Inhibitors Animal Experiments Animals Anti-Inflammatory Agents Anti-inflammatory Antiviral Agents Bacteria Bacterial Infections Binding Biological Availability Coupled Development Diet Disease Progression Dose Drug usage Family Genetic Polymorphism Hypertension In Situ In Vitro Inflammatory Bowel Diseases Inflammatory Response Inflammatory disease of the intestine Intestinal Absorption Intestines Intravenous Kidney Kinetics Knockout Mice Laboratories Malignant Neoplasms Mediating Mind Molecular Monobactams N-formylmethionyl-leucyl-phenylalanine Nitrogen Nucleosides Nutritional Oligopeptides Oral Administration Organ Pathogenesis Peptide Transport Peptides Permeability Pharmaceutical Preparations Physiological Play Process Prodrugs Property Proteins Protons Resources Role Safety Structure Substrate Specificity System Testing Therapeutic Agents Time Study Tissues Vascular blood supply Virus Diseases Work absorption design drug efficacy human subject improved in vivo insight interest lysylproline member mimetics new therapeutic target novel peptidomimetics public health relevance response uptake valacyclovir

项目摘要

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.

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的生理学、药理学和病理学作用及其相关性。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。

项目成果

期刊论文数量（77）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Competitive inhibition of p-aminohippurate transport by quinapril in rabbit renal basolateral membrane vesicles.

喹那普利对兔肾基底外侧膜囊泡中对氨基马尿酸转运的竞争性抑制。

DOI：
10.1023/a:1023281325479
发表时间：
1998
期刊：
Journal of pharmacokinetics and biopharmaceutics
影响因子：
0
作者：
Akarawut,W;Smith,DE
通讯作者：
Smith,DE

Mouse endogenous retroviruses can trigger premature transcriptional termination at a distance.

DOI：
10.1101/gr.130740.111
发表时间：
2012-05
期刊：
Genome research
影响因子：
7
作者：
Li J;Akagi K;Hu Y;Trivett AL;Hlynialuk CJ;Swing DA;Volfovsky N;Morgan TC;Golubeva Y;Stephens RM;Smith DE;Symer DE
通讯作者：
Symer DE

Expression and regulation of the proton-coupled oligopeptide transporter PhT2 by LPS in macrophages and mouse spleen.