MODELS FOR GENETIC DISORDERS

描述（改编自申请人摘要）：研究者的 长期目标是详细了解 参与分泌和吸收离子的离子转运蛋白的功能， 胃肠道和肾脏对酸/碱和电解质的控制 体内平衡 为了实现这一目标，他们正在使用基因靶向 技术来检查特定转运蛋白的体内功能。 他们 已经为NHE 1，2和3 Na/H交换剂开发了无效突变小鼠， 结肠和胃H，K-ATP酶（cHKA和gHKA），噻嗪敏感性 NaCl协同转运蛋白和基底外侧NaK 2C 1协同转运蛋白（NKCC 1）。 目标1 该建议是开发NHE 4 Na/H交换器的无效突变小鼠， AE 2和NBC 1/HCO 3交换剂、NBC 1 Na/HCO 3协同转运蛋白和C1 C-2 C1通道，并对其表型进行初步分析。 在目标2中， 胃HC 1和KC 1分泌和粘膜的转运机制 将对保护进行分析。 这些研究将检验以下假设： C1 C-2、AE 2和NHE 4是胃壁分泌HCl所必需的 NHE 2在粘膜保护和维持壁细胞中发挥作用， 在酸分泌过程中的细胞活力; NKCC 1是最大限度地 KC 1由胃腺分泌。 在目标3中， 将分析肠道中的吸收和分泌。 这些 研究将测试以下各项的功能：作为顶端C1/HCO 3交换器的CO2 介导C1吸收; AE 2作为基底外侧C1/HCO 3交换器介导 HCO 3吸收; NHE 1和NKCC 1在毒素刺激分泌中; NHE 2在钝化中 腹泻状态的严重程度;以及结肠和结肠中K再循环中的cHKA。 为腹泻状态提供补偿。 在目标4中， 特异性转运蛋白在肾功能中的相对重要性 分析了 在这些研究中，他们将：分析小鼠的肾脏表型 缺乏NKCC 1、AE 2和NHE 2;在HCO 3中检测cHKA和gHKA的功能 集合管重吸收和尿钾保存 在钾耗竭期间;并分析NBC 1和 NHE 3在近端小管重吸收HCO 3和酸碱平衡中的作用。 这些研究将大大扩展我们对特定的 单个转运蛋白的功能以及它们如何共同作用 体内跨上皮离子转运过程。

DESCRIPTION (Adapted from the Applicant's Abstract): The investigator's long-term objective is to develop a detailed understanding of the physiological functions of ion transporters involved in secretion and absorption of ions in the gastrointestinal tract and in renal control of acid/base and electrolyte homeostasis. In working toward this goal, they are using gene-targeting technology to examine the in vivo functions of specific transporters. They have already developed null mutant mice for the NHE1,2 and 3 Na/H exchangers, the colonic and gastric H,K-ATPases (cHKA and gHKA), the thiazide-sensitive NaCl cotransporter, and the basolateral NaK2C1 cotransporter (NKCC1). Aim 1 of this proposal is to develop null mutant mice for the NHE4 Na/H exchanger, the AE2 and DRA C1/HCO3 exchangers, the NBC1 Na/HCO3 cotransporter, and the C1C-2 C1 channel, and to perform the initial analyses of their phenotypes. In Aim 2, the transport mechanisms underlying gastric HC1 and KC1 secretion and mucosal protection will be analyzed. These studies will test the hypotheses that C1C-2, AE2, and NHE4 are essential for HC1 secretion by the gastric parietal cell; that NHE2 functions in mucsosa protection and in maintaining parietal cell viability during acid secretion; and that NKCC1 is required for maximum KC1 secretion by gastric glands. In Aim 3, the transport mechanisms underlying absorption and secretion in the intestinal tract will be analyzed. These studies will test the functions of: DRA as the apical C1/HCO3 exchanger mediating C1 absorption; AE2 as the basolateral C1/HCO3 exchanger mediating HCO3 absorption; NHE1 and NKCC1 in toxin-stimulated secretion; NHE2 in blunting the severity of diarrhea states; and cHKA in K recycling in the colon and in providing compensation for diarrhea states. In Aim 4, the function and relative importance of specific transporters in renal function will be analyzed. In these studies they will: analyze the renal phenotypes of mice lacking NKCC1, AE2, and NHE2; test the functions of cHKA and gHKA in HCO3 reabsorption in the collecting duct and in urinary potassium conservation during potassium depletion; and analyze the relative importance of NBC1 and NHE3 in HCO3 reabsorption in the proximal tubule and in acid-base homeostasis. These studies will substantially expand our understanding of the specific functions of individual transporters and how they work together to mediate transepethelial ion transport processes in vivo.