Role of PEPT2 in Peptide/Mimetic Disposition-Dynamics

细胞、分子和生理学研究对机械学做出了重大贡献 了解PEPT2的结构、功能和定位。然而，这些实验性的方法是 通常受限于体外设计和缺乏血液供应，重叠的底物特异性，以及 多种运输系统的贡献，其中一些在研究时尚不为人所知。因此，它是 很难，如果不是不可能的话，很难定义单个特定基因产物的功能及其在 与感兴趣的组织或器官中存在的其他可能的蛋白质的关系。长期的形容词 这一相互竞争的更新申请的目的是定义生理和药理作用以及 PEPT2，一个营养和药物转运体的相关性。我们的工作假设是PEPT2是主要的 负责多肽和多肽类药物在体内的处置和动态的转运体， 尤其是大脑和肾脏。为了验证这一假设，提出了以下具体目标：目标1.至 明确PEPT2在影响体内药代动力学、组织分布中的作用和相对重要性 和全身性暴露的多肽和多肽类药物；目的2.确定区域影响 PEPT2对小鼠脑脊液多肽外流的影响及其对药理作用的影响 脑；目的3.表征PEPT2在脑中的细胞定位和功能活性 发育中的小鼠的实质。通过将膜、细胞、免疫定位和整体动物相结合 在野生型和PEPT2缺失小鼠中的研究，所提出的研究将极大地促进我们对 PEPT2在体内对多肽底物和药物的作用、意义和载体转运(与之相反 其他潜在的运输者)。这些研究也可能提供难得的洞察力 具有遗传多态的受试者的多肽/模拟动力学和反应。最后， 拟议的研究可能对基于多肽的设计、递送和靶向具有重要意义 治疗严重中枢神经系统疾病的药物。LAV描述：该项目将决定 特定转运体PEPT2影响多肽和多肽类药物在肾脏和肾脏中的处置 大脑。这些研究的结果将提高治疗感染、高血压和高血压的药物的安全性和有效性 癌症，并促进开发治疗脑部疾病(如阿尔茨海默病、艾滋病)的新药。

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-termobjectives 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).