Role of PepT1 in Intestinal Inflammation

描述（由申请人提供）： PepT 1是质子寡肽转运蛋白（POT）超家族的成员。众所周知，PepT 1转运二肽/三肽，但不转运游离氨基酸或具有三个以上氨基酸残基的肽。还公认PepT 1主要在小肠的上皮细胞中表达，并且在正常小肠的这些细胞中以低水平存在或根本不存在。当我们开始研究PepT 1时，没有已知的人类病理学与转运蛋白相关。自从我们的研究开始以来，我们已经证明了在发炎但非发炎的结肠上皮细胞中表达的人肠二肽和三肽转运蛋白hPepT 1介导小促炎细菌肽如甲酰-Met-Leu-Phe（fMLP）、胞壁酰二肽（MDP）和L-Ala-β-D-Glu-meso-DAP（Tri-DAP）转运到结肠上皮细胞的胞质溶胶中。一旦进入细胞质， 细菌肽可以与胞内受体的核苷酸结合位点-富含亮氨酸重复序列（NBS-LRR）家族的成员相互作用，并引发肠道炎症反应。重要的是，已经表明（另一个广泛引用我们工作的小组）PepT 1多态性与IBD相关。总体而言，我们的研究表明，PepT 1可能与人类肠道疾病（IBD）的发病机制有关。我们的总体假设是，结肠PepT 1在启动和维持肠结肠炎中起着关键作用，因此参与结肠炎相关癌症的发展。该提案的最初目的是研究结肠炎相关癌症中的PepT 1-NOD 2信号通路。其次，我们将探讨结肠PepT 1表达在结肠屏障功能减弱和影响伤口愈合中的作用，这可能是IBD中结直肠癌发展的重要决定因素。最后，使用纳米技术方法，我们将研究PepT 1治疗肠道炎症和结肠炎相关癌症的靶向作用。据设想，计划的工作将确定PepT 1在结肠炎相关癌症中的功能作用的分子机制，并允许开发针对肠道炎症条件的治疗策略。对退伍军人医疗保健的影响：美国有超过100万成年人，包括VA人群，患有IBD，每年诊断出约50，000例新病例（根据美国克罗恩病和结肠炎基金会。VA IBD患者的结直肠癌发病率比一般人群高得多（2.9%对0.1%;来自国家卫生统计中心数据）。因此，了解IBD的病因和相关的病理机制是寻求开发有效的未来治疗方法的研究的主要目标，将直接使退伍军人受益。

DESCRIPTION (provided by applicant): PepT1 is a member of the Proton Oligopeptide Transporter (POT) superfamily. PepT1 is well known to transport di/tripeptides, but not free amino acids or peptides with more than three amino acid residues. It is also well recognized that PepT1 is mostly expressed in epithelial cells of the small intestine and is present at low levels, or not at all, in such cells of the normal lare intestine. When we initiated our studies on PepT1, no known human pathology was associated with the transporter. Since the inception of our research, we have demonstrated that the human intestinal di- and-tri-peptide transporter, hPepT1, which is expressed in inflamed but not non-inflamed colonic epithelial cells, mediates the transport of small pro-inflammatory bacterial peptides such as formyl-Met-Leu-Phe (fMLP), muramyl dipeptide (MDP) and L-Ala- -D-Glu-meso-DAP (Tri- DAP), into the cytosol of colonic epithelial cells. Once in the cytosol, these small bacterial peptides can interact with members of the Nucleotide Binding Site-Leucine-Rich Repeat (NBS-LRR) family of intracellular receptors and initiate intestinal inflammatory responses. Importantly it has been shown (by another group that extensively cited our work) that a PepT1 polymorphism is associated with IBD. Overall, our studies have revealed that PepT1 may be associated with the pathogenesis of intestinal bowel disease (IBD) in humans. Our overall hypothesis is that colonic PepT1 plays a critical role in initiating and perpetuating intestinal colitis and consequently participate to the development of colitis associated cancer. The initial aim of this proposal is to investigate the PepT1-NOD2 signaling pathway(s) in colitis associated cancer. Second, we will explore the role of colonic PepT1 expression in weakness colonic barrier function and affecting wound healing that may an important determinant of colorectal cancer development in IBD. Finally, using nanotechnology approaches, we will investigate the targeting of PepT1 for treatment of intestinal inflammation and colitis associated cancer. It is envisaged that the planned work will identify the molecular mechanisms underlying the functional role of PepT1 in colitis associated cancer and allow development of therapeutic strategies targeting intestinal inflammatory conditions. Impact on Veterans Health care: Over one million adults in the US, including members of the VA population, suffer from IBD, and about 50,000 new cases are diagnosed each year (according to the Crohn's and Colitis Foundation of America. The VA IBD patients have a much higher rate of colorectal cancer compared to the general population (2.9% vs. 0.1%; from National Center for Health Statistics data). Thus, attaining an understanding of the etiology of IBD and the relevant pathological mechanisms are major aims of research seeking to develop effective future treatments will directly benefit the veteran population.