hPepT1 in Intestinal Inflammation

hPepT1 在肠道炎症中的作用

• 批准号: 7929146
• 负责人: DIDIER MERLIN
• 金额: $ 5.44万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-25 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7929146
• 关键词: 6-Mercaptopurine; Acetylmuramyl-Alanyl-Isoglutamine; Adrenal Cortex Hormones; Adult; Adverse effects; Aminosalicylate; Anti-Inflammatory Agents; Anti-inflammatory; Azathioprine; Bacteria; Binding Sites; Biochemical; Cell Communication; Cell membrane; Cells; Chemotactic Factors; Child; Chronic; Colitis; Colon; Cytosol; Data; Development; Dipeptides; Disease; Epithelial; Epithelial Cells; Epithelium; Etiology; Family; Gastrointestinal tract structure; Gene Expression; Genetic; Genus Cola; Immune; Immune response; Immune system; Immunosuppressive Agents; In Vitro; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Inflammatory disease of the intestine; Intestines; Investigation; Lamina Propria; Large Intestine; Lead; Leucine-Rich Repeat; MHC Class I Genes; Measures; Mediating; Membrane; Membrane Microdomains; Microbe; Molecular; Movement; Mucositis; Mus; N-Formylated Peptide; NF-kappa B; Nucleotides; Oligopeptides; Pathogenesis; Pathway interactions; Patients; Peptide Hydrolases; Peptides; Play; Research; Role; Therapeutic; Tissues; Toxic effect; Transcriptional Activation; United States; Wild Type Mouse; Wound Healing; base; basolateral membrane; brush border membrane; clinical care; cytokine; design; enteropathogenic Escherichia coli; improved; in vivo; insight; macrophage; member; neutrophil; novel therapeutics; overexpression; receptor; therapeutic development; uptake

Project Summary Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the digestive tract with an uncertain etiology. At present, treatment of IBD is limited to 5-aminosalicylates, corticosteroids, and immunosuppressants, including azathioprine and 6-mercaptopurine. Because specific and curative treatments with acceptable toxicity and side effect profiles are lacking, there remains a demand for the development of effective therapeutic approaches. Of significant importance to the present application are our findings from previous studies, which demonstrated that bacterial products, such as fMLP and MDP, could be transported by the intestinal epithelial oligopeptide transporter, PepT1. Once taken up into the cytosol, these small bacterial peptides initiate an inflammatory response. These bacterial peptides can also interact directly with immune cells. Since immune cells, including macrophages, also express PepT1, they have the capacity to take up small bacterial peptides, which can then interact with the NBS- LRR family of intracellular receptors (e.g., NOD2) that mediate intracellular recognition of microbes and their products. Thus, together with the inflammatory response initiated at the epithelial level, these small bacterial peptides in immune system cells may lead to an inflammatory cascade that results in tissue damage. Our overall hypothesis is that PepT1 plays a critical role in regulating the immune response by serving as a gateway for bacterial products. The initial aim of this proposal is to investigate the induction of PepT1 expression in colonic epithelial cells. Secondly, we will investigate the role of immune cell-expressed PepT1 in intestinal inflammation using chimeric mice. Finally, PepT1 will be used to target the anti-inflammatory tripeptide, KPV, to inflamed colonic epithelial and immune cells. The project will involve a variety of biochemical and molecular approaches at both the in vitro and in vivo level. The proposed study will generate new insights that will be key to the design and development of therapeutic strategies to ameliorate intestinal inflammatory conditions, including IBD. More than one million adults and children in the United States suffer from IBD. New therapeutic strategies based on a better understanding of the pathogenesis of IBD will improve the clinical care of patients with this disorder.

项目概要 炎症性肠病（IBD）是一种消化道慢性炎症性疾病， 病因不明。目前，IBD的治疗仅限于5-氨基水杨酸盐​​， 皮质类固醇和免疫抑制剂，包括硫唑嘌呤和6-巯基嘌呤。 因为具有可接受的毒性和副作用的特异性和治疗性治疗是 如果缺乏，仍然需要开发有效的治疗方法。 对于本应用来说非常重要的是我们之前的研究结果，其中 证明细菌产物，例如 fMLP 和 MDP，可以通过 肠上皮寡肽转运蛋白，PepT1。一旦被吸收到细胞质中，这些小 细菌肽引发炎症反应。这些细菌肽也可以相互作用 直接与免疫细胞作用。由于包括巨噬细胞在内的免疫细胞也表达 PepT1， 它们有能力吸收小细菌肽，然后与 NBS-相互作用 LRR 细胞内受体家族（例如 NOD2）介导细胞内识别 微生物及其产品。因此，连同在 在上皮水平上，免疫系统细胞中的这些小细菌肽可能会导致 炎症级联反应导致组织损伤。 我们的总体假设是 PepT1 通过以下方式在调节免疫反应中发挥着关键作用： 作为细菌产品的门户。该提案的最初目的是调查 诱导结肠上皮细胞中 PepT1 的表达。其次，我们要探讨的角色 使用嵌合小鼠研究免疫细胞表达的 PepT1 在肠道炎症中的作用。最后，PepT1 将 用于靶向抗炎三肽 KPV，以治疗发炎的结肠上皮和 免疫细胞。 该项目将涉及体外和体外的各种生物化学和分子方法。 和体内水平。拟议的研究将产生新的见解，这对设计至关重要 和开发改善肠道炎症的治疗策略， 包括炎症性肠病。 美国有超过一百万成人和儿童患有炎症性肠病 (IBD)。新疗法 基于更好地了解 IBD 发病机制的策略将改善临床治疗 护理患有这种疾病的患者。