Role of PEPT2 in Peptide/Mimetic Disposition-Dynamics

描述（由申请人提供）：细胞、分子和生理学研究对PEPT 2结构、功能和定位的机制理解做出了重大贡献。然而，这些实验方法通常受到体外设计和缺乏血液供应、重叠底物特异性以及多种转运系统的影响的限制，其中一些在研究时是未知的。因此，如果不是不可能的话，也很难定义单个特定基因产物的功能及其相对于存在于感兴趣的组织或器官中的其他可能的蛋白质的意义。这一竞争性更新申请的长期目标是确定PEPT 2（一种营养物质和药物转运蛋白）的生理和药理作用及其相关性。我们的工作假设是PEPT 2是负责肽和肽样药物在体内，特别是脑和肾内的处置和动力学的主要转运蛋白。为了检验这一假设，提出了以下具体目的：目的1：确定PEPT 2在影响肽和肽样药物的体内药代动力学、组织分布和全身暴露方面的作用和相对重要性;目的2：确定PEPT 2对肽从脑脊液流出的区域影响及其对脑中药理学反应的影响;目的3：表征PEPT 2在发育小鼠脑实质中的细胞定位和功能活性。通过结合野生型和PEPT 2缺失小鼠中的膜、细胞、免疫定位和整个动物研究，所提出的研究将极大地促进我们对PEPT 2（与其他潜在转运蛋白相反）的肽底物和药物的体内作用、意义和载体转运的理解。这些研究也可能提供罕见的洞察肽/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。最后，所提出的研究可能对基于肽的药物的设计、递送和靶向脑以治疗严重CNS疾病具有重要意义。LAV说明：该项目将确定一种特定的转运蛋白PEPT 2如何影响肽和肽样药物在肾脏和大脑中的分布。这些研究的结果将提高治疗感染、高血压和癌症药物的安全性和有效性，并促进治疗脑部疾病（例如，阿尔茨海默病、艾滋病）。

DESCRIPTION (provided by applicant): Cellular, molecular and physiological studies have made major contributions toward a mechanistic understanding of PEPT2 structure, function and localization. However, these experimental approaches are often limited by an in vitro design and lack of blood supply, overlapping substrate specificities, and the contribution of multiple transport systems, some of which are unknown at the time of study. As a result, it is difficult, if not impossible, to define the function of a single specific gene product and its significance in relation to other possible proteins that are present in the tissue or organ of interest. The long-term objectives of this competing renewal application are to define the physiological and pharmacological roles and relevance of PEPT2, a nutrient and drug transporter. Our working hypothesis is that PEPT2 is the primary transporter responsible for the disposition and dynamics of peptides and peptide-like drugs within the body, particularly the brain and kidney. To test this hypothesis, the following specific aims are proposed: Aim 1: To define the role and relative importance of PEPT2 in affecting the in vivo pharmacokinetics, tissue distribution and systemic exposure of peptides and peptide-like drugs; Aim 2: To determine the regional influence of PEPT2 on peptide efflux from the cerebrospinal fluid and its influence on pharmacologic response in the brain; Aim 3: To characterize the cellular localization and functional activity of PEPT2 in the brain parenchyma of developing mice. By combining membrane, cellular, immunolocalization and whole animal studies in wild type and PEPT2 null mice, the proposed studies will greatly advance our understanding of the in vivo role, significance and vectorial transport of peptide substrates and drugs by PEPT2 (as opposed to other potential transporters). These studies may also provide rare insight into the variability of peptide/mimetic kinetics and response in those human subjects with genetic polymorphisms. Finally, the proposed studies may have important implications for the design, delivery and targeting of peptide-based Pharmaceuticals to the brain for severe CNS disorders. Lav Description: This project will determine how a specific transporter, PEPT2, affects the disposition of peptides and peptide-like drugs in the kidney and brain. Results from these studies will improve the safety and efficacy of drugs for infection, hypertension and cancer, and facilitate the development of new drugs for brain disorders (e.g., Alzheimer's disease, AIDS).