Regulation of Intestinal Iron Transfer

肠道铁转运的调节

• 批准号: 6706208
• 负责人: DAVID J HAILE
• 金额: $ 18.06万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6706208
• 关键词: RNase protection assay; chemical structure function; dietary iron; disease /disorder model; duodenum; free radicals; gastrointestinal epithelium; gastrointestinal nutrient absorption; genetic promoter element; genetic regulation; genetic strain; genetic transcription; genetic translation; immunocytochemistry; in situ hybridization; intracellular; iron metabolism; laboratory mouse; messenger RNA; microcytic /hypochromic anemia; nucleic acid structure; nutrition related tag; protein transport; tissue /cell culture; transferrin

Iron is the most abundant transition metal in the human body and an essential nutrient. Toxicity results when cellular free iron catalyzes the formation of destructive free radicals. Aging, atherosclerosis, arthritis, are some of the increasing list of human conditions in which iron catalyzed generation of free radicals is suspected to contribute to tissue injury. To minimize toxicity, the iron content of the body tightly regulates uptake of iron through the duodenal epithelium. The central hypothesis of this application is that the control of duodenal iron export is primarily transcriptional and that this transcriptional control is independent of duodenal epithelial cell iron content. This hypothesis has been formulated on the basis of strong preliminary evidence from my laboratory that a) the regulation of MTP1 by iron is the opposite of the regulation observed with other 5' IRE containing genes, such as ferritin, b) the duodenal epithelial expression of MTP1 is independent of iron content of the epithelial cell itself. I plan to test the hypothesis and accomplish the objectives of this grant proposal by completing the following specific aims: 1. Measure MTP1 mRNA and protein levels and transcription rates in duodenal sections of normal, mk, sla and hpx mice with varying amounts of total body iron. 2. Determine the structure of the 5' UTR of the MTP1 mRNA induced with iron deprivation in duodenal epithelial cells. 3. Characterize the role of the 5' UTR IRE of MTP1 in the iron dependent regulation of the gene. This approach is expected to yield the following results: a) Identification of the mode of regulation of MTP1 by iron in the duodenum. b) Characterization of the role of the differing 5' UTRs of MTP1 in the iron dependent regulation of the gene. Identification of the mechanisms of the regulation by iron of components responsible for iron absorption will result in a better understanding of overall iron metabolism and will lead to better therapeutic strategies for limiting cellular damage secondary to iron derived free radicals.

铁是人体中最丰富的过渡金属，也是必需的营养素。 当细胞无铁催化破坏性自由基的形成时，会产生毒性。衰老，动脉粥样硬化，关节炎是人类条件的越来越多的列表，其中铁催化的自由基被怀疑会导致组织损伤。 为了最大程度地减少毒性，人体的铁含量严格调节铁上皮的摄取。 该应用的中心假设是对十二指肠铁的输出的控制主要是转录的，并且该转录控制与十二指肠上皮细胞铁含量无关。 这一假设是根据我的实验室的强有力的初步证据提出的，a）铁对铁的调节是与其他5'含有基因的调节相反的，例如铁蛋白，例如铁蛋白，b）Mtp1的十二指肠上皮表达与上皮细胞本身的铁含量独立于上皮细胞本身的铁含量。 我计划通过完成以下特定目的来检验假设并实现该赠款提案的目标：1。测量MTP1 mRNA和蛋白质水平和蛋白质水平和转录速率，在正常，MK，SLA和HPX小鼠的十二指肠部分中使用总体铁的不同量。 2。确定在十二指肠上皮细胞中用铁剥夺诱导的MTP1 mRNA的5'UTR的结构。 3。表征MTP1 5'UTR在基因的铁依赖调节中的作用。 预计这种方法将产生以下结果：a）十二指肠铁中铁对MTP1的调节方式鉴定。 b）表征MTP1不同5'UTR在基因依赖性调节中的作用。 通过铁铁对铁吸收的组件来识别调节机制，将使对整体铁代谢有更好的了解，并将带来更好的治疗策略，以限制继发于铁衍生的自由基的细胞损伤。