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: 8820221
• 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/8820221
• 关键词: Acute; Affect; Atherosclerosis; Attenuated; Bacterial Translocation; Cell Line; 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; Lysophospholipids; Macronutrients Nutrition; Maintenance; Malignant Neoplasms; Malnutrition; Mediating; Military Personnel; Minerals; Modality; Modeling; Molecular; Morbidity - disease rate; Mus; Nutrient; 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; Work; Wound Healing; absorption; alkylglycerophosphoethanolamine phosphodiesterase; cancer cell; cell motility; cell type; cytokine; extracellular; gastrointestinal; improved; in vivo; injury and repair; intestinal crypt; intestinal homeostasis; intestinal villi; 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，影响了美国超过100万人。 IBD是一个经常的原因 美国退伍军人的住院。 IBD增加了其他疾病（例如大肠癌和动脉粥样硬化）的危险因素。肠中的极化上皮在炎症中起着重要作用，它是入侵病原体与宿主的免疫系统之间的障碍。上皮损害会损害营养和矿物质的吸收，通常导致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中的敌对环境至关重要。肠上皮增殖和迁移是伤口愈合的要求，这是IBD中破坏的过程。溶物磷脂酸（LPA）是一种具有不同生长因子样作用的脂质介质。细胞外LPA是通过称为自动西昔辛（ATX）的溶血磷脂酶D对循环的溶血磷脂水解产生的。 LPA的作用是通过G蛋白偶联受体的家族介导的：LPA1R-LPA5R。 LPA1R是小肠和结肠中最丰富的LPA受体，但LPA1R的功能意义知之甚少。该应用的推动力来自我们最近的发现，即肠结果中LPA1R的损失增加了对硫酸葡萄糖钠（DSS） - 通过延迟恢复过程而诱发的结肠炎。我们旨在进一步定义LPA1R在慢性炎症中的重要性，并确定LPA1R如何调节肠上皮稳态（AIM 1）。 LPA通常被视为促炎剂。我们发现，在DSS介导的结肠炎中，产生LPA的ATX的表达水平增加了，缺乏ATX表达的小鼠对DSS诱导的结肠炎的抗性。但是，ATX的缺失或ATX的化学抑制显着延迟了DSS诱导的损伤的恢复。因此，LPA在炎症和恢复开始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标。我们将使用ATX的遗传缺失和化学抑制来评估对急性和慢性炎症的影响（AIM 2）。 IBD，特别是患有克罗恩病的人，由于营养吸收率降低和/或大量营养素的损失增加，患有多种营养缺乏症的风险。 LPA1R的缺失或抑制降低了营养和电解质的几种转运蛋白的表达。相反，用LPA处理小鼠的小鼠增加了转运蛋白的表达，这表明LPA在肠道吸收功能方面起了有益的作用。我们建议评估是否可以使用LPA来增强与IBD相关的上皮吸收功能（AIM 3）。该应用的总体目标是研究LPA在维持肠上皮稳态方面的重要性，并调节上皮屏障和吸收功能的调节。拟议工作的成功完成应更好地理解LPA1R介导的作用，该作用与拟议的有关主要LPA产生的ATX的研究一起，将使维持健康的肠道维持，并为治疗炎症性疾病的治疗提供潜在的治疗方式。