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.

Pept1是质子寡肽转运蛋白（POT）超家族的成员，众所周知 运输DI/三肽。我们的小组和其他人表明，Pept1在 小肠，但在正常大肠的此类细胞中以低或无法检测到的水平存在。在 此外，我们证明了结肠PEPT1表达在结肠炎和结肠炎相关的 癌症（CAC）。通过在PEPT1表达中生成功能丧失和功能丧失的鼠标模型。 肠上皮细胞（IEC），我们探索了Pept1在肠内稳态，炎症和 结肠炎相关的肿瘤发生。我们还检查了Pept1的表达和运输活动 结肠炎和CAC的小鼠模型，并进一步揭示了该膜转运蛋白的功能不是 仅限于其作为二肽转运蛋白的经典功能。例如，我们证明了Pept1 表达通过介导肠道miRNA的表达/分泌有助于维持肠道稳态。 重要的是，我们在最后一个融资周期中证明了pept1 - / - 微生物群/代谢组就足够了 防止结肠炎和CAC。当前建议的总体目标是开发药物输送 治疗结肠炎的平台。该提案的最初目的是调查是否口服藻酸盐 水凝胶负载的PEPT1 - / - 微生物群将增强供体微生物群的植入动力学/多样性 因此增强了结肠炎的预防/治疗。在第二个目标中，我们将探索细胞 PEPT1 - / - 微生物群的靶标，并评估随后降低结肠炎的肠细胞反应。 最后，我们将表征和评估口服特定的体内预防性效果 来自PEPT1 - / - 菌群中的抗炎代谢产物，加载到纳米颗粒中。拟议的研究将 促进针对肠道炎症和结肠炎的治疗溶液的发展 癌症状况。