GPR120 regulation of inflammatory bowel disease

GPR120对炎症性肠病的调节

• 批准号: 10153774
• 负责人: Yingzi Cong
• 金额: $ 50.09万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10153774
• 关键词: Agonist; Anti-Inflammatory Agents; Antigens; Appetite Regulation; Biological; CD4 Positive T Lymphocytes; Cell physiology; Cells; Chronic; Colitis; Crohn' s disease; Cytochrome P450; Dendritic Cells; Development; Diabetes Mellitus; Diet; Dietary Component; Dietary Factors; Dietary Fats; Dietary Fatty Acid; Dietary Intervention; Disease; Energy-Generating Resources; Enzymes; Epithelial Cells; FRAP1 gene; Flagellin; G-Protein-Coupled Receptors; Gene Expression; Genes; Homeostasis; IRF1 gene; Immune; In Vitro; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Insulin Resistance; Intake; Interferon Type II; Interleukin-10; Interleukin-17; Interleukin-6; Intestines; Kinetics; Knockout Mice; Lamina Propria; Ligands; Metabolic Diseases; Mucous Membrane; Mus; N-3 polyunsaturated fatty acid; Nonesterified Fatty Acids; Nutrient; Omega-3 Fatty Acids; Omega-6 Fatty Acids; Oral; Pathogenesis; Pathway interactions; Patients; Pediatric Crohn' s disease; Play; Polyunsaturated Fatty Acids; Production; Regulation; Research; Risk; Role; STAT3 gene; Signaling Molecule; T cell regulation; T cell response; T-Lymphocyte; Testing; Therapeutic; Transgenic Mice; Transgenic Organisms; Ulcerative Colitis; Up-Regulation; Variant; Wild Type Mouse; alpha-Linolenic Acid; antigen-specific T cells; beta catenin; cell type; dietary; fatty acid metabolism; glucose uptake; gut microbiota; in vivo; infancy; inflammatory disease of the intestine; insight; intestinal epithelium; intestinal homeostasis; lipid biosynthesis; long chain fatty acid; microbiota; mouse model; new therapeutic target; novel; pre-clinical; preservation; prevent; receptor; response; therapeutic target

ABSTRACT Increasing evidence suggest that the interactions between diet and the gut microbiota may play a critical role in promoting or alleviating intestinal inflammation. However, little is known about the mechanisms involved. Free fatty acids provide important energy sources as dietary nutrients, and act as signaling molecules in various cellular processes. Most notable among the free fatty acids’ targets are mammalian G protein-coupled receptors. GPR120 (also known as free fatty acid receptor 4, FFAR4) has been identified as a receptor for long-chain fatty acids (LCFA) from dietary products, and has a critical role in various physiological homeostasis mechanisms, such as adipogenesis, and regulation of appetite. Its agonists are suggested as therapeutic targets for diabetes, metabolic disorders and inflammatory diseases. Various ω-3 or ω-6 polyunsaturated FAs activate GPR120 in the micromolar concentration range. GPR120 agonism by various ligands, more particularly by the omega 3 (ω- 3, n-3; α-linolenic acid, ALA) polyunsaturated fatty acids (PUFA), has been shown to result in varied potentially beneficial biological effects. However, the mechanisms involved are still largely unknown. It is also unknown if and how GPR120 regulates intestinal homeostasis. We have established recently that GPR120-/- mice developed more severe colitis upon inflammatory insult, and administration of GPR120 agonist inhibited colitis development. We showed that both T cells and dendritic cells (DC) expressed GPR120 in addition to IEC and other cells. Transfer of GPR120-/- CD4+ T cells from CBir1 TCR transgenic (CBir1 Tg) mice, which are specific for an immunodominant microbiota antigen CBir1 flagellin, induced more severe colitis in Rag-/- mice with decreased IL-10 producing T cells in the intestinal lamina propria compared to wild-type (WT) T cells. In this application, we hypothesize that GPR120 contributes to intestinal homeostasis through regulation of T cell and DC function, which leads to preservation of intestinal immune homeostasis and inhibition of inflammatory bowel diseases. Furthermore, GPR120 agonists will prevent and treat colitis. We will define the mechanisms by which GPR120 regulates T cell function (Aim 1), and intestinal DC function (Aim 2). Finally we will determine the effects of GPR120 agonists in preventing and treating colitis (Aim 3). This highly translational project will provide novel insights into dietary intervention of IBD and point to GPR120 as a potential therapeutic target for treatment of IBD patients.

摘要 越来越多的证据表明，饮食和肠道微生物群之间的相互作用可能在 促进或者减轻肠道炎症。然而，人们对所涉及的机制知之甚少。免费 脂肪酸作为膳食营养素提供重要的能量来源，并在各种疾病中充当信号分子。 细胞过程在游离脂肪酸的靶点中，最值得注意的是哺乳动物G蛋白偶联受体。 GPR 120（也称为游离脂肪酸受体4，FFAR 4）已被鉴定为长链脂肪酸的受体。 酸（LCFA），并在各种生理稳态机制中具有关键作用， 如脂肪生成和食欲调节。其激动剂被建议作为糖尿病的治疗靶点， 代谢紊乱和炎性疾病。不同的ω-3或ω-6多不饱和脂肪酸激活GPR 120， 微摩尔浓度范围。通过各种配体，更具体地通过ω 3（ω-ω 3）的GPR 120激动 3，n-3; α-亚麻酸，ALA）多不饱和脂肪酸（PUFA），已被证明会导致各种潜在的 有益的生物效应。然而，所涉及的机制在很大程度上仍然是未知的。目前还不清楚是否 以及GPR 120如何调节肠道内稳态。我们最近已经确定，GPR 120-/-小鼠发展为 炎症损伤后结肠炎更加严重，并且给予GPR 120激动剂抑制了结肠炎的发展。 我们发现，除了IEC和其他细胞外，T细胞和树突状细胞（DC）都表达GPR 120。 来自CBirlTCR转基因（CBirlTg）小鼠的GPR 120-/-CD 4 + T细胞的转移，所述细胞对免疫球蛋白具有特异性。 免疫显性微生物群抗原CBir 1鞭毛蛋白在Rag-/-小鼠中诱导了更严重的结肠炎， 与野生型（WT）T细胞相比，肠固有层中产生IL-10的T细胞。在本申请中，我们 假设GPR 120通过调节T细胞和DC功能而有助于肠内稳态， 这导致肠免疫稳态的保持和炎性肠病的抑制。 此外，GPR 120激动剂将预防和治疗结肠炎。我们将定义GPR 120 调节T细胞功能（Aim 1）和肠DC功能（Aim 2）。最后，我们将确定 GPR 120激动剂在预防和治疗结肠炎中的作用（目的3）。这个高度翻译的项目将提供新颖的 深入了解IBD的饮食干预，并指出GPR 120是治疗IBD的潜在治疗靶点。 IBD患者