PepT1-/- microbiota therapy as a treatment for colitis

PepT1-/- 微生物群疗法作为结肠炎的治疗方法

• 批准号: 10363142
• 负责人: DIDIER MERLIN
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10363142
• 关键词: Adult; Affect; Alginates; Americas; Anti-Inflammatory Agents; Bacteria; Cell physiology; Cells; Colitis; Colon; Colorectal Cancer; Data; Diagnosis; Down-Regulation; Drug Delivery Systems; Engraftment; Epithelial Cells; Etiology; Foundations; Funding; Future; General Population; Genetic; Goals; Healthcare; Hydrogels; Immune system; Inflammation; Inflammatory; Intestinal permeability; Intestines; Large Intestine; Mediating; Membrane Transport Proteins; Metabolic; MicroRNAs; Modification; Mucosal Immune Responses; Mucous body substance; Mus; Oligopeptides; Oral; Oral Administration; Pathologic; Patients; Phenotype; Population; Predisposition; Prevention; Proteomics; Protons; Research; Role; Severities; Small Intestines; Testing; United States National Center for Health Statistics; Up-Regulation; Variant; Veterans; Wild Type Mouse; cell type; cellular targeting; colitis associated cancer; dextran sulfate sodium induced colitis; experimental study; fecal transplantation; genome-wide; gut inflammation; in vivo; intestinal epithelium; intestinal homeostasis; large bowel Crohn' s disease; loss of function; member; metabolome; microbiota; microbiota transplantation; military veteran; mouse model; murine colitis; nanoparticle; novel; prevent; response; therapeutic development; tumorigenesis

PepT1, which is a member of the proton oligopeptide transporter (POT) superfamily, is well known to transport di/tripeptides. Our group and others have shown that PepT1 is highly expressed in epithelial cells of the small intestine, but present at low or undetectable levels in such cells of the normal large intestine. In addition, we have demonstrated that colonic PepT1 expression is up-regulated in colitis and colitis-associated cancer (CAC). By generating gain- and loss-of-function mouse models with PepT1 expression specifically in intestinal epithelial cells (IECs), we explored the role of PepT1 in intestinal homeostasis, inflammation, and colitis-associated tumorigenesis. We also examined the expression and transport activities of PepT1, using mouse models of colitis and CAC, and further revealed that the function of this membrane transporter is not restricted to its classical function as a transporter of di-tripeptides. For example, we demonstrated that PepT1 expression helps maintain intestinal homeostasis by mediating intestinal miRNA expression/secretion. Importantly we demonstrated during the last funding cycle that the PepT1-/- microbiota/metabolome is sufficient to protect against colitis and CAC. The overall goal of the current proposal is to develop a drug delivery platform to treat colitis. The initial aim of this proposal will be to investigate whether oral delivery of alginate hydrogel-loaded PepT1-/- microbiota will enhance the engraftment dynamics/diversity of the donor microbiota and consequently enhance the prevention/treatment of colitis. In the second aim, we will explore the cellular targets of PepT1-/- microbiota and assess the subsequent intestinal cellular responses that decrease colitis. Finally, we will characterize and assess the in vivo colitis-preventing effects of oral administration of specific anti-inflammatory metabolites from PepT1-/- microbiota loaded into nanoparticles. The proposed research will facilitate the development of therapeutic solutions targeting intestinal inflammatory and colitis associated cancer conditions.

PepT 1是质子寡肽转运蛋白（POT）超家族的成员， 转运二肽/三肽。我们的研究小组和其他人已经表明，PepT 1在上皮细胞中高度表达， 在小肠中，但在正常大肠的这些细胞中以低水平或不可检测的水平存在。在 此外，我们已经证明结肠PepT 1表达在结肠炎和结肠炎相关性结肠炎中上调， 癌症（CAC）。通过产生具有PepT 1表达的功能获得和丧失小鼠模型， 肠上皮细胞（IEC），我们探讨了PepT 1在肠道内稳态，炎症， 结肠炎相关的肿瘤发生。我们还研究了PepT 1的表达和转运活性， 小鼠结肠炎和CAC模型，并进一步揭示了这种膜转运蛋白的功能不是 仅限于其作为二-三肽转运蛋白的经典功能。例如，我们证明PepT 1 表达通过介导肠miRNA表达/分泌来帮助维持肠内稳态。 重要的是，我们在上一个资助周期中证明了PepT 1-/-微生物群/代谢组是足够的。 预防结肠炎和CAC当前提案的总体目标是开发一种药物递送 治疗结肠炎的平台。这项建议的最初目的是调查是否口服藻酸盐 水凝胶负载的PepT 1-/-微生物群将增强供体微生物群的植入动力学/多样性 从而增强结肠炎的预防/治疗。在第二个目标中，我们将探索细胞 PepT 1-/-微生物群的靶点，并评估随后减少结肠炎的肠道细胞反应。 最后，我们将描述和评估口服特定的抗结肠炎药物的体内结肠炎预防效果。 将来自PepT 1-/-微生物群的抗炎代谢物加载到纳米颗粒中。拟议的研究将 促进开发针对肠道炎症和结肠炎相关的治疗解决方案 癌症状况