Regulation of a Novel Intestinal NHE Isoform (NHE8)

新型肠道 NHE 亚型 (NHE8) 的调节

• 批准号: 8332260
• 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/8332260
• 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.

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NHE 8（Na+/H+交换异构体8; SLC 9A 8）的研究，NHE 8是一个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。NHE 8在许多组织中表达，包括肠和肾中上皮细胞的顶膜。在上一个资助期间，我们从肠道中克隆了NHE 8，并描述了其在发育过程中的调控。此外，我们发现NHE 8在生命早期的顶端Na+/H+交换中起着重要作用，并且它补偿了NHE 2-/-xNHE 3-/-小鼠中NHE 2和NHE 3的损失。我们已经开发了一种新的NHE 8缺乏症动物模型，并计划在这次更新中，表征NHE 8在胃肠道和男性生殖系统中的作用。 我们的中心假设是NHE 8对于最佳HCO 3-转运是必需的，如通过NHE 8-/-小鼠中NH3（在腺瘤中下调; SLC 26 A3）和PAT 1（推定的阴离子转运蛋白1，SLC 26 A6）的下调所证明的。由于HCO 3-是线粒体呼吸的副产物，并且对于加速CO2废物处理是必不可少的，因此HCO 3-转运的下调导致细胞和全身酸碱平衡的失控。HCO 3-转运功能障碍是多种疾病的基础和后果。基于从NHE 8-/-小鼠的表型分析获得的初步数据，我们计划了三个具体的目标来研究NHE 8的作用，即其损失对胃肠道和生殖系统发育的后果。 三个具体目标是：1）发育期间NHE 8-/-小鼠的表型表征; 2）NHE 8在胃肠道中和响应上皮损伤的作用的表征;和3）NHE 8在睾丸功能中的作用的表征。 这些研究是新颖的，将产生新的见解NHE 8的作用，包括在上皮细胞中的离子通量的调节一般。