Fecal exosomes as a source of miRNA biomarkers for diagnosing the degree of colitis and as a drug delivery system to reduce colitis

粪便外泌体作为 miRNA 生物标志物的来源，用于诊断结肠炎的程度，并作为减少结肠炎的药物输送系统

基本信息

批准号：
9982320
负责人：
Timothy L Denning
金额：
$ 44.5万
依托单位：
GEORGIA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-20 至 2024-07-31
项目状态：
已结题

项目摘要

Summary In addition to secreting soluble mediators, colonic epithelial cells also secrete exosomes (a type of nanovesicle) that contain epigenetic material (proteins, transcription factors, RNAs, miRNAs and DNA fragments). Exosomes are thought to be released basolaterally into the mucosa, where they may regulate local innate responses, and apically, where they may functionally modulate cells at a distance along the gastrointestinal tract and regulate the homeostasis of gut microbiota. In the proposed work, we will exclusively focus on the apical secretion of exosomes into the lumen. Our preliminary results demonstrate that exosomes secreted into the lumen by colonic epithelial cells transit along the gastrointestinal tract and are present in feces. Importantly, colonic and fecal exosomes are similar in their sizes (~140 nm) and miRNA compositions, suggesting that exosomes protect the loaded epigenetic material from highly destructive elements, such as the catabolic enzymes found in the gastrointestinal lumen. Our central hypothesis is that fecal exosomes could yield new miRNA biomarker signatures that may be used to diagnose the degree of colitis and as a drug delivery system to reduce colitis. Our first aim will be to examine the effects of colitis on fecal exosomes, with the aim of identifying new miRNAs that may be used as an intestinal biomarker signature that reflects disease severity. In Aim 2, we will examine whether the microbiota composition can be modulated by the administration of various miRNA panels. In Aim 3, we will examine whether orally administered autologous-healthy fecal exosomes, either alone or as a drug carrier, can reduce intestinal inflammation. It is envisaged that the proposed experiments will facilitate the identification of new biomarkers signatures for intestinal inflammation and allow the development of new therapeutic strategies.

概括除了分泌可溶性介质外，结肠上皮细胞还分泌外泌体（一种纳米层）其中包含表观遗传材料（蛋白质，转录因子，RNA，miRNA和DNA片段）。外泌体被认为可以在基底外侧释放到粘膜中，他们可能会规范当地的先天反应，并且顶端，它们可能在功能上调节沿胃肠道的距离的细胞并调节肠道微生物群的稳态。在拟议的工作中，我们将专注于外泌体的顶端分泌进入管腔。我们的初步结果表明，外皮被结肠上皮分泌到管腔中细胞沿胃肠道转运，并存在于粪便中。重要的是，结肠和粪便外泌体是它们的尺寸相似（〜140 nm）和miRNA组成，表明外泌体保护了荷载表观遗传学来自高度破坏性元素的材料，例如在胃肠道腔中发现的分解代谢酶。我们的中心假设是粪便外泌体可能会产生新的miRNA生物标志物特征诊断结肠炎的程度和作为减少结肠炎的药物输送系统。我们的第一个目标是检查结肠炎对粪便外泌体的影响，目的是识别可用作肠道的新miRNA 反映疾病严重程度的生物标志物签名。在AIM 2中，我们将检查微生物群的组成是否可以通过管理各种miRNA面板来调节。在AIM 3中，我们将检查是否口头单独或作为药物携带者，管理的自体健康外泌体可以减少肠道炎。可以预见，提出的实验将有助于识别新的生物标志物肠道炎症的签名，并允许发展新的治疗策略。