pH Regulation of Fat Storage in the Nematode Intestine

线虫肠道脂肪储存的 pH 调节

• 批准号: 6952415
• 负责人: Keith Nehrke
• 金额: $ 31.2万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-27 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6952415
• 关键词: Caenorhabditis elegans; RNA interference; Xenopus; acid base balance; acidosis; biological signal transduction; cell line; cholesterol; dietary restriction; fluorescence microscopy; functional /structural genomics; gastrointestinal absorption /transport; gene deletion mutation; genetic mapping; genetic screening; glucose metabolism; lipid metabolism; longevity; membrane transport proteins; microarray technology; mitochondria; oxygen consumption; protein isoforms; protein localization; recombinant proteins; sodium hydrogen exchanger; suppressor mutations

DESCRIPTION (provided by applicant): Deficiencies in Na+/H+ or CI-/HCO3- exchange compromise fluid and electrolyte transport in the mammalian intestine, but the ultimate role of acid-base transport in nutrient uptake processes and lipid metabolism is relatively poorly understood. In addition, little is known regarding how intestinal pHi influences cell signaling events that response to nutrient availability. We hypothesis that pHi acts as a synergistic messenger, and provides a metabolic context through which the actions of diverse cellular and trans-cellular signaling pathways are interpreted. In this application, we offer preliminary evidence linking acid-base transport to fat storage and related signaling events in the nematode C. elegans, and propose the following: Aim 1 involves characterizing the SLC4 and SLC26 CI-/HCO3- homologs in C. elegans by first assessing their distribution, then examining function both in situ, using recombinant protein expression and in vivo, using a genetically encoded pH indicator and RNAi. Aim 2 is designed to test how changes in intestinal pHi affect classic cell signaling processes that regulate fat storage, and conversely what cell signaling processes are involved in conveying the phenotypic effects of cellular acidosis. Aim 3 is designed to utilize genetic, reverse-genetic, and functional genomic assays to identify regulatory proteins that attenuate intracellular pH, as well as the global transcriptional responses to intracellular acidification. The strength of this proposal is that it will use a powerful model system and novel reagents for monitoring pH in living organisms to study fat biology from a unique perspective: that of acid-base homeostasis.

描述（由申请人提供）：