Regulation of Na absorption by NHE3 in the intestine

NHE3 在肠道中对钠吸收的调节

• 批准号: 7693700
• 负责人: Changhyon Chris Yun
• 金额: $ 32.94万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7693700
• 关键词: Acute; Attenuated; Biological Factors; Caco-2 Cells; Cardiovascular system; Chronic; Colon; Coupled; Data; Development; Dexamethasone; Diarrhea; Disease; Epithelial Cells; Experimental Models; Gene Expression; Glucocorticoids; Glycerophospholipids; Goals; Grant; Hormones; In Vitro; Inflammation; Intestines; Knockout Mice; Lysophospholipids; Malabsorption Syndromes; Mediating; Membrane; Metabolic; Metabolism; Modality; Molecular; Mus; NHE1; NHE2; Outcome; Phospholipase; Phosphorylation; Phosphotransferases; Physiological; Play; Process; Protein Isoforms; Proteins; Regulation; Role; Scaffolding Protein; Serum; Side; Signal Pathway; Sodium Chloride; Surface; Testing; Therapeutic; Transcriptional Activation; Transcriptional Regulation; Transgenic Animals; Transport Process; Water; absorption; base; ezrin; improved; in vivo; intestinal epithelium; lysophosphatidic acid; mRNA Expression; public health relevance; receptor; response; sodium-hydrogen exchanger regulatory factor; trafficking

DESCRIPTION (provided by applicant): The Na+/H+ exchanger isoform 3 (NHE3) constitutes a major Na+ transport process, which moves a large quantity of salt and water from the mucosal side toward the serosal side. Our long-term goal is to understand the molecular mechanisms that control NHE3 activity in the intestine. Because NHE3 is often targeted in many diarrheal diseases and the mechanisms underlying inhibition of NHE3 have often been studied. However, the mechanisms and biological factors activating NHE3 are less well understood. This is an important aspect as a better understanding of the mechanisms activating NHE3 should aid the development of improved therapeutic modalities to counteract diarrhea caused by inhibition of Na+/H+ exchange. The goals of this application are to delineate the mechanisms of NHE3 activation by glucocorticoids and lysophosphatidic acid (LPA). In the previous grant, we investigated the regulation of NHE3 by glucocorticoids, which is a major hormone activating NHE3 under physiologic and pathophysiologic conditions. Our studies revealed that the serum and glucocorticoid-inducible kinase 1 (SGK1) plays a central role in regulation of NHE3. Moreover, transcriptional regulation of NHE3 gene expression by glucocorticoids is not sufficient to result in an increase in NHE3 activity. Glucocorticoids activate SGK1, which phosphorylates NHE3 and facilitates trafficking of NHE3 protein to the surface membrane. A goal of this application is to further delineate the roles of SGK1 and the NHE regulatory factor 2 (NHERF2) in vivo using transgenic animals. We will also test a specific hypothesis that SGK2 plays a role in activation of NHE3 in the intestine. In addition to glucocorticoids, we recently found that LPA is a potent activator of NHE3 in intestinal epithelial cells. We hypothesize that LPA activates NHE3 via LPA5 receptor, which is highly expressed in the intestine. We will define the mechanism of LPA- mediated activation of NHE3 and determine the physiologic effect of LPA on NHE3. In Aim 1, we will investigate regulation of NHE3 by dexamethasone in vivo and determine the role of SGK2. In Aim 2 and Aim 3, we propose to determine the mechanism of LPA-mediated activation of NHE3 and determine its effect in an experimental model of diarrhea. PUBLIC HEALTH RELEVANCE: The Na+/H+ exchanger 3 (NHE3) is the major Na+ absorptive process in the intestine and colon and is frequently inhibited in many diarrheal diseases. The goals of this application are to determine the effects of glucocorticoids and lysophosphatidic acids and to delineate the mechanisms resulting in the activation of NHE3. The outcome of the proposed studies should enhance our understanding of the regulation of NHE3 and may aid in the development of improved therapeutic modalities to neutralize diarrhea caused by Na+ malabsorption.

描述（由申请人提供）：NA+/H+交换器同工型3（NHE3）构成了一个主要的Na+运输过程，该过程将大量的盐和水从粘膜侧移至浆膜侧。我们的长期目标是了解控制肠中NHE3活性的分子机制。因为NHE3通常是针对许多腹泻疾病的，因此经常研究NHE3抑制的机制。但是，激活NHE3的机制和生物因素知之甚少。这是一个重要方面，因为对激活NHE3的机制的更好理解应有助于改善治疗方式来抵消由Na+/H+交换抑制引起的腹泻。该应用的目标是描述糖皮质激素和溶血磷脂酸（LPA）的NHE3激活机制。在上一个赠款中，我们研究了糖皮质激素对NHE3的调节，糖皮质激素是生理和病理生理条件下的一种主要激活NHE3的激素。我们的研究表明，血清和糖皮质激素诱导激酶1（SGK1）在NHE3调节中起着核心作用。此外，糖皮质激素对NHE3基因表达的转录调节不足以导致NHE3活性的增加。糖皮质激素激活SGK1，该SGK1磷酸化NHE3并促进将NHE3蛋白运输到表面膜上。该应用的目的是进一步描述使用转基因动物在体内在体内的SGK1和NHE调节因子2（NHERF2）的作用。我们还将检验一个特定的假设，即SGK2在肠中NHE3的激活中起作用。除了糖皮质激素外，我们最近发现LPA是肠上皮细胞中NHE3的有效活化剂。我们假设LPA通过LPA5受体激活NHE3，该受体在肠中高度表达。我们将定义LPA介导的NHE3激活的机制，并确定LPA对NHE3的生理效应。在AIM 1中，我们将通过地塞米松在体内调查NHE3的调节，并确定SGK2的作用。在AIM 2和AIM 3中，我们建议确定LPA介导的NHE3激活的机理，并在腹泻实验模型中确定其作用。公共卫生相关性：NA+/H+交换器3（NHE3）是肠和结肠中的主要Na+吸收过程，并且在许多腹泻疾病中经常被抑制。该应用的目标是确定糖皮质激素和溶血磷脂酸的作用，并描绘导致NHE3激活的机制。拟议研究的结果应增强我们对NHE3调节的理解，并可能有助于发展改善治疗方法，以中和由Na+不良吸收引起的腹泻。