INVESTIGATION OF REGULATORY SEQUENCES IN THE PACAP-1 RECEPTER PROMOTER

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。以前的研究表明，适当的离子交换和跨壁细胞膜的运输对于正常的胃酸分泌是必不可少的。例如，缺乏Na+/H+交换器Nhe2和Nhe4、Cl2/HCO3交换器AE2和K+通道Kvlqt1的基因工程小鼠表现出显著的酸分泌障碍。此外，胃泌素缺乏的小鼠表现出胃水通道水通道4(Aqp4)和氯通道Clca3表达的改变。这些基因在胚胎发育期间或随着小鼠年龄增长而在胃中表达的模式尚不清楚。胃酸分泌被认为是在分娩前立即开始的；此外，有证据表明，随着老鼠年龄的增长，胃酸分泌也会增加。了解Aqp4、Clca3、Nhe2、Nhe4、AE2、Kir2.1和Kvlqt1在发育和衰老小鼠中的表达模式，可能会为酸分泌的开始时间以及与年龄相关的酸水平增加提供线索。本研究的总体目标是分析Aqp4、Clca3、Nhe2、Nhe4、AE2、Kir2.1和Kvlqt1等多种与正常酸分泌有关的通道和交换器的发育和年龄相关表达。这项研究的假设是，这些基因的胃部表达在胚胎发育后期增加，并随着成年小鼠年龄的增长而增加。具体目标1将侧重于胚胎发育过程中候选分子的基因表达分析和胃免疫定位。特定目标2将分析这些候选基因和蛋白质在衰老野生型和胃泌素缺陷小鼠中的表达模式。确定这些基因在小鼠胚胎发育和衰老小鼠中的表达模式，将有助于更彻底地了解调节胃酸分泌系统的机制。这项研究将进一步阐明胃酸分泌的发育和年龄相关的调节，从而对胃肠生物学领域产生影响。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Previous studies have shown that proper ion exchange and transport across the parietal cell membrane is essential for normal gastric acid secretion. For example, genetically engineered mice deficient for the Na+/H+ exchangers Nhe2 and Nhe4, the Cl-/HCO3 exchanger Ae2, and the K+ channel Kvlqt1 showed significant impairments in acid secretion. In addition, achlorhydric gastrin-deficient mice showed alterations in gastric expression of the water channel aquaporin-4 (Aqp4) and the chloride channel Clca3. The patterns of gastric expression of these genes during embryonic development or as mice age is unknown. Gastric acid secretion is thought to be initiated immediately before parturition; in addition, evidence suggests that there is an increase in gastric acid secretion as mice age. Understanding the expression patterns of Aqp4, Clca3, Nhe2, Nhe4, Ae2, Kir2.1, and Kvlqt1 both in development and in aging mice may yield clues as to the timing of initiation of acid secretion as well as the age-related increase in acid levels. The overall goal of this research is to analyze developmental and age-related expression of various channels and exchangers important for normal acid secretion, including Aqp4, Clca3, Nhe2, Nhe4, Ae2, Kir2.1, and Kvlqt1. The hypothesis of this study is that the gastric expression of these genes increases at later embryonic developmental stages and increases as adult mice age. Specific Aim 1 will focus on gene expression analysis and gastric immunolocalization of candidate molecules during embryonic development. Specific Aim 2 will analyze gene and protein expression patterns of these candidates in aging wild-type and gastrin-deficient mice. Determining the expression patterns of these genes in murine embryonic development as well as in aging mice will allow a more thorough understanding of mechanisms that that regulate the gastric acid secretory system. This research will have an impact on the field of gastrointestinal biology by further elucidating the developmental and age-related regulation of gastric acid secretion.