Role of PEPT2 in Peptide/Mimetic Disposition-Dynamics

细胞、分子和生理学研究已经对一种机制做出了重大贡献。 了解PEPT 2的结构、功能和定位。然而，这些实验方法 通常受限于体外设计和缺乏血液供应、重叠的底物特异性， 多个运输系统的贡献，其中一些是未知的研究时。因此， 很难，如果不是不可能的话，定义一个单一的特定基因产物的功能及其在人类疾病中的意义。 与存在于感兴趣的组织或器官中的其他可能的蛋白质的关系。长期宾语 这一竞争性更新应用的目的是定义生理和药理作用， PEPT 2是一种营养和药物转运蛋白。我们的工作假设是PEPT 2是主要的 负责肽和肽样药物在体内的处置和动力学的转运蛋白， 尤其是大脑和肾脏为了检验这一假设，提出了以下具体目标：目标1。到 定义PEPT 2在影响体内药代动力学、组织分布 和肽和肽样药物的全身暴露;目的2.为了确定区域影响， PEPT 2对脑脊液中肽流出的影响及其对药物反应的影响 大脑;目标3.表征PEPT 2在脑中的细胞定位和功能活性 发育中小鼠的薄壁组织。通过结合膜、细胞、免疫定位和整个动物 在野生型和PEPT 2敲除小鼠中的研究，所提出的研究将大大促进我们对 肽底物和药物通过PEPT 2的体内作用、意义和载体转运（与 其他潜在的运输商）。这些研究也可能提供罕见的洞察力的变化， 肽/模拟物动力学和具有遗传多态性的那些人类受试者的反应。最后 提出的研究可能对基于肽的药物的设计、递送和靶向具有重要意义。 用于治疗严重中枢神经系统疾病的药物。LAV描述：这个项目将确定如何在一个 特异性转运蛋白PEPT 2影响肽和肽样药物在肾脏中的分布， 个脑袋这些研究的结果将提高治疗感染、高血压和糖尿病的药物的安全性和有效性。 癌症，并促进脑疾病新药的开发（例如，阿尔茨海默病、艾滋病）。

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).