Involvement of Na/Dicarboxylate Cotransporter in Aging

钠/二羧酸协同转运蛋白参与衰老

• 批准号: 6479293
• 负责人: Ana M Pajor
• 金额: $ 7.45万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6479293
• 关键词: age difference; aging; caloric dietary content; complementary DNA; dicarboxylate; dietary restriction; gene environment interaction; gene expression; genetic promoter element; genetic regulation; human genetic material tag; laboratory mouse; longevity; membrane transport proteins; messenger RNA; northern blottings; nutrition related tag; polymerase chain reaction; protein localization; sodium ion; western blottings

The focus of the current proposal is the mammalian Na+/dicarboxylate co-transporter, NaDC-1, which is expressed on the apical membranes of the epithelial cells of the small intestine and kidney proximal tubule. NaDC-1 transports the metabolic intermediates of the Krebs cycle, including citrate and succinate. This transporter is the mammalian homolog of the Drosophila Indy gene product that has been implicated in determining lifespan. Mutations that lead to a partial inactivation of Indy produce an increase in lifespan, similar to the effects of caloric restriction in mammals. The results suggest that a reduction in the activity of NaDC-1 by inactivation or by reducing its substrates may produce the metabolic changes that lead to increased longevity. The long-term objective of this research is to determine the feasibility of using NaDC-1 as a target protein to mimic the effects of caloric restriction. Our group has a longstanding interest in the transporters related to NaDC-1 and we have cloned the NaDC-1 orthologs form human, rabbit and mouse. The studies in this proposal will use the cDNAs coding for the mouse and human NaDC-1 to produce preliminary data in two areas: first, relating the activity of NaDC-1 in aging and caloric restriction, and second, identifying factors that regulate the activity of NaDC-1.

当前提案的重点是哺乳动物Na+/二羧酸协同转运蛋白NaDC-1，它在小肠和肾近曲小管上皮细胞的顶膜上表达。 NaDC-1 运输三羧酸循环的代谢中间产物，包括柠檬酸盐和琥珀酸盐。这种转运蛋白是果蝇 Indy 基因产物的哺乳动物同源物，与决定寿命有关。导致 Indy 部分失活的突变会延长寿命，类似于哺乳动物热量限制的效果。结果表明，通过灭活或减少其底物来降低 NaDC-1 的活性可能会产生代谢变化，从而延长寿命。这项研究的长期目标是确定使用 NaDC-1 作为靶蛋白来模拟热量限制效果的可行性。我们的小组对与 NaDC-1 相关的转运蛋白有着长期的兴趣，我们已经从人类、兔子和小鼠中克隆了 NaDC-1 直向同源物。该提案中的研究将使用编码小鼠和人类 NaDC-1 的 cDNA 来产生两个领域的初步数据：第一，将 NaDC-1 的活性与衰老和热量限制相关；第二，确定调节 NaDC-1 活性的因素。