Regulation of a Novel Intestinal NHE Isoform (NHE8)

新型肠道 NHE 亚型 (NHE8) 的调节

• 批准号: 8242516
• 负责人: Fayez Khalaf Ghishan
• 金额: $ 32.95万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8242516
• 关键词: Acid-Base Equilibrium; Acids; Address; Adult; Age; Animal Model; Apical; Architecture; Bicarbonates; Blood; Brain; Buffers; Carbon Dioxide; Carrier Proteins; Cell Culture Techniques; Cell physiology; Chemistry; Coupled; Data; Development; Diet; Down-Regulation; Electrolytes; Epidermal Growth Factor; Epithelial; Epithelial Cells; Excision; Eye; Family; Funding; Gastric ulcer; Gastrointestinal Contents; Gastrointestinal tract structure; Gene Expression Regulation; Genes; Glucocorticoids; Goblet Cells; Homeostasis; Incidence; Inflammatory disease of the intestine; Injury; Intervention; Intestines; Ions; Kidney; Kinetics; Life; Liquid substance; Liver; Male Genital Organs; Male Sterility; Measures; Mitochondria; Modeling; Mucin-2 Staining Method; Mucins; Mus; NHE2; Nutrient; Pathology; Pharmacologic Substance; Phenotype; Physiological; Play; Predisposition; Process; Production; Protein Isoforms; Public Health; Refuse Disposal; Regulation; Reproductive Health; Reproductive system; Research; Respiration; Role; SLC26A3 gene; Source; Sperm Capacitation; Spermatogenesis; Staging; Sterility; System; Systems Development; Testis; Tissues; Urine; Volatile Fatty Acids; Water; absorption; apical membrane; base; design; fatty acid transport; gastrointestinal; gastrointestinal system; insight; leydig interstitial cell; male; meetings; member; novel; postnatal; putative anion transporter 1; reproductive; reproductive development; response; wasting

DESCRIPTION (provided by applicant): This is a competing renewal application designed to continue our studies on NHE8 (Na+/H+ exchanger isoform 8; SLC9A8), the newest member of a family of transport proteins involved in many cellular functions regulated through electroneutral Na+/H+ exchange. NHE8 is expressed in many tissues including the apical membrane of the epithelial cells in the intestine and the kidney. During the last funding period, we cloned NHE8 from the intestine and characterized its regulation during development. Furthermore, we showed that NHE8 plays a major role in apical Na+/H+ exchange during early life, and it compensates for the loss of NHE2 and NHE3 in NHE2-/-xNHE3-/- mice. We have developed a novel animal model of NHE8 deficiency and plan, in this renewal, to characterize the role of NHE8 in the gastrointestinal tract and the male reproductive system. Our central hypothesis is that NHE8 is essential for optimal HCO3- transport as evidenced by the down- regulation of DRA (down-regulated in adenoma; SLC26A3) and PAT1 (putative anion transporter 1, SLC26A6) in NHE8-/- mice. Because HCO3- is the byproduct of mitochondrial respiration and is essential for accelerating CO2 waste disposal, down regulation of HCO3- transport results in loss of control of cellular and systemic acid- base balance. Dysfunctional HCO3- transport is the basis of and a consequence of a variety of maladies. Based on the preliminary data obtained from phenotypic analysis of NHE8-/- mice, we have planned three specific aims to investigate the role of NHE8, the consequence of its loss on gastrointestinal and reproductive system development. The three specific aims are: 1) Phenotypic characterization of NHE8-/- mouse during development; 2) Characterization of the role of NHE8 in the gastrointestinal tract and in response to epithelial injury; and 3) Characterization of the role of NHE8 in testicular function. The studies are novel and will yield new insight into the role of NHE8 to include regulation of ion fluxes in epithelial cells in general. PUBLIC HEALTH RELEVANCE: This proposed research is relevant to public health because determining the physiological role of NHE8 and studying its mechanism of regulating bicarbonate transport will enhance our understanding of epithelial transport.

描述（由申请人提供）：这是一项竞争性更新申请，旨在继续我们对 NHE8（Na+/H+ 交换异构体 8；SLC9A8）的研究，NHE8 是转运蛋白家族的最新成员，参与通过电中性 Na+/H+ 交换调节的许多细胞功能。 NHE8在许多组织中表达，包括肠和肾上皮细胞的顶膜。在上一个资助期间，我们从肠道克隆了 NHE8，并表征了其在发育过程中的调节。此外，我们发现NHE8在生命早期的顶端Na+/H+交换中发挥着重要作用，并且它补偿了NHE2-/-xNHE3-/-小鼠中NHE2和NHE3的损失。我们开发了一种新型 NHE8 缺陷动物模型，并计划在本次更新中表征 NHE8 在胃肠道和男性生殖系统中的作用。 我们的中心假设是 NHE8 对于最佳 HCO3- 转运至关重要，NHE8-/- 小鼠中 DRA（腺瘤中下调；SLC26A3）和 PAT1（推定阴离子转运蛋白 1，SLC26A6）的下调证明了这一点。由于 HCO3- 是线粒体呼吸的副产品，对于加速 CO2 废物处理至关重要，因此 HCO3- 运输的下调会导致细胞和全身酸碱平衡失控。 HCO3- 运输功能失调是多种疾病的基础和后果。根据 NHE8-/- 小鼠表型分析获得的初步数据，我们计划了三个具体目标来研究 NHE8 的作用，以及 NHE8 缺失对胃肠道和生殖系统发育的影响。 三个具体目标是：1）NHE8-/-小鼠在发育过程中的表型特征； 2) NHE8在胃肠道中的作用以及对上皮损伤的反应的表征； 3) NHE8 在睾丸功能中的作用的表征。 这些研究是新颖的，将对 NHE8 的作用产生新的见解，包括对上皮细胞中离子通量的总体调节。 公共健康相关性：这项拟议的研究与公共健康相关，因为确定 NHE8 的生理作用并研究其调节碳酸氢盐转运的机制将增强我们对上皮转运的理解。