Regulation of intestinal homeostasis and epithelial barrier by LPA

LPA 对肠道稳态和上皮屏障的调节

• 批准号: 9337341
• 负责人: Changhyon Chris Yun
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9337341
• 关键词: Acute; Affect; Atherosclerosis; Attenuated; Bacterial Translocation; Cells; Chemicals; Chronic; Colitis; Colon; Colon Carcinoma; Colorectal Cancer; Communities; Crohn' s disease; Disease; Electrolytes; Environment; Enzymes; Epithelial; Epithelial Cell Proliferation; Epithelial Cells; Epithelium; Etiology; Experimental Models; Family; Future; G-Protein-Coupled Receptors; Genetic; Goals; Growth Factor; Health; Homeostasis; Hospitalization; Hydrolysis; Ileitis; Immune; Immune response; Immune system; Immunity; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Injury; Intestinal Mucosa; Intestines; Invaded; Leukocytes; Lysophosphatidic Acid Receptors; Lysophospholipase; Lysophospholipids; Macronutrients Nutrition; Maintenance; Malignant Neoplasms; Malnutrition; Mediating; Military Personnel; Minerals; Modality; Modeling; Molecular; Morbidity - disease rate; Mus; Nutrient; Pathogenicity; Patients; Permeability; Play; Predisposition; Process; Production; Proliferating; Recovery; Regulation; Resistance; Risk; Risk Factors; Role; Signal Transduction; Small Intestines; Sodium Dextran Sulfate; Therapeutic; Ulcerative Colitis; United States; Veterans; Villus; Work; Wound Healing; absorption; cancer cell; cell motility; cell type; cytokine; extracellular; gastrointestinal; improved; in vivo; injury and repair; intestinal crypt; intestinal homeostasis; lipid mediator; lysophosphatidic acid; microorganism; migration; novel; nutrient absorption; pathogen; public health relevance; repaired; restoration; solute; vzg-1 Receptor

DESCRIPTION (provided by applicant): PROJECT SUMMARY Inflammatory bowel diseases (IBD), including Crohn's disease and ulcerative colitis, affect more than 1 million people in the United States. IBD is a frequent cause of hospitalization among US military veterans. IBD increases the risk factor for other diseases such as colorectal cancer and atherosclerosis. Polarized epithelia in the intestine play an important role in inflammation by serving as a barrier between an invading pathogen and the immune system of the host. Damage to the epithelia compromises absorption of nutrients and mineral, often leading to malnutrition in patients with IBD. Hence, the ability to maintain the epithelial barrier integrity is critical in protecting the host from a hostile environment in the intestinal lumen. Intestinal epithelial proliferation and migration are requirements in wound healing, a process disrupted in IBD. Lysophosphatidic acid (LPA) is a lipid mediator with diverse growth factor-like effects. Extracellular LPA is produced by hydrolysis of circulating lysophospholipid by a lysophospholipase D known as autotaxin (ATX). The effects of LPA are mediated through a family of G protein- coupled receptors: LPA1R-LPA5R. LPA1R is the most abundant LPA receptor in the small intestine and colon, and yet the functional significance of LPA1R is poorly understood. The impetus of this application came from our recent findings that loss of LPA1R in the intestine results increased susceptibility to dextran sulfate sodium (DSS)- induced colitis by delaying the recovery process. We aim to further define the importance of LPA1R in chronic inflammation and determine how LPA1R regulates intestinal epithelial homeostasis (Aim 1). LPA is often regarded as a pro-inflammatory agent. We found that the expression level of LPA-producing ATX was increased in DSS- mediated colitis, and mice deficient in ATX expression showed resistance to DSS-induced colitis. However, deletion of ATX or chemical inhibition of ATX significantly delayed recovery from DSS-induced injury. Hence, LPA appear to have opposing effects during the onset of inflammation and recovery. We propose to investigate whether ATX is a potential target in treatment of intestinal inflammation. We will use genetic deletion and chemical inhibition of ATX to assess the effects on acute and chronic inflammation (Aim 2). Individuals with IBD and, particularly, those with Crohn's disease are at risk for a variety of nutritional deficiencies because of decreased nutrient absorption and/or increased losses of macronutrients. Deletion or inhibition of LPA1R decreased expression of several transporters of nutrients and electrolytes. On the contrary, treating mice with spontaneous ileitis with LPA increased transporter expression, suggesting a beneficial role of LPA on the intestinal absorptive function. We propose evaluate whether LPA could be used to enhance epithelial absorptive functions associated with IBD (Aim 3). The overarching goal of this application is to investigate the importance of LPA in maintenance of intestinal epithelial homeostasis and regulation of the epithelial barrier and absorptive functions. Successful completion of the proposed work should provide a better understanding of the LPA1R- mediated effects, which together with the proposed study on the major LPA-producing ATX, will benefit maintenance of healthy intestine and provide potential therapeutic modality for treatment of inflammatory diseases.

描述（由申请人提供）： 项目摘要 炎症性肠病 (IBD)，包括克罗恩病和溃疡性结肠炎，影响着美国超过 100 万人。 IBD 是一个常见原因 美国退伍军人住院治疗的情况。 IBD 增加了结直肠癌和动脉粥样硬化等其他疾病的危险因素。肠道中的极化上皮作为入侵病原体和宿主免疫系统之间的屏障，在炎症中发挥着重要作用。上皮细胞损伤会影响营养物质和矿物质的吸收，常常导致 IBD 患者营养不良。因此，维持上皮屏障完整性的能力对于保护宿主免受肠腔恶劣环境的影响至关重要。肠上皮增殖和迁移是伤口愈合的必要条件，而 IBD 则破坏了这一过程。溶血磷脂酸 (LPA) 是一种脂质介质，具有多种生长因子样作用。细胞外 LPA 是通过称为自分泌运动因子 (ATX) 的溶血磷脂酶 D 水解循环溶血磷脂而产生的。 LPA 的作用是通过 G 蛋白偶联受体家族介导的：LPA1R-LPA5R。 LPA1R 是小肠和结肠中最丰富的 LPA 受体，但人们对 LPA1R 的功能意义知之甚少。这项应用的推动力来自我们最近的发现，即肠道中 LPA1R 的缺失会延迟恢复过程，从而增加对葡聚糖硫酸钠 (DSS) 诱导的结肠炎的易感性。我们的目标是进一步明确 LPA1R 在慢性炎症中的重要性，并确定 LPA1R 如何调节肠上皮稳态（目标 1）。 LPA 通常被认为是一种促炎剂。我们发现，在 DSS 介导的结肠炎中，产生 LPA 的 ATX 表达水平增加，并且 ATX 表达缺陷的小鼠表现出对 DSS 诱导的结肠炎的抵抗力。然而，ATX 的缺失或 ATX 的化学抑制显着延迟了 DSS 引起的损伤的恢复。因此，LPA 在炎症发生和恢复期间似乎具有相反的作用。我们建议研究 ATX 是否是治疗肠道炎症的潜在靶点。我们将利用 ATX 的基因缺失和化学抑制来评估对急性和慢性炎症的影响（目标 2）。患有IBD的个体，特别是患有克罗恩病的个体，由于营养吸收减少和/或常量营养素损失增加而面临各种营养缺乏的风险。 LPA1R 的缺失或抑制会降低几种营养物和电解质转运蛋白的表达。相反，用 LPA 治疗患有自发性回肠炎的小鼠会增加转运蛋白的表达，表明 LPA 对肠道吸收功能具有有益作用。我们建议评估 LPA 是否可用于增强与 IBD 相关的上皮吸收功能（目标 3）。该应用的首要目标是研究 LPA 在维持肠上皮稳态以及调节上皮屏障和吸收功能中的重要性。成功完成拟议的工作应该可以更好地理解 LPA1R 介导的作用，与拟议的对主要产生 LPA 的 ATX 的研究一起，将有利于维持健康的肠道，并为治疗炎症性疾病提供潜在的治疗方式。