Molecular Mechanisms of Active Copper Transport

项目总结 铜是人体生长发育和正常功能所必需的物质。中存在的缺陷 铜稳态与包括孟克斯病、威尔逊病在内的一系列病理因素有关 疾病、梅德尼克综合征和其他疾病。到目前为止，对人体铜稳态的研究主要集中在 铜转运蛋白和铜小载体的功能及其调控。有了这个学习计划，我们将 开始了解哺乳动物的铜转运蛋白及其调节器是如何协同工作来调节营养的 在肠道内转运。小肠负责吸收所有必需的营养物质。我们 发现肠细胞中铜的有效性强烈影响乳糜粒的丰度， 饮食脂肪的主要载体。我们还发现脂肪反应蛋白ANKRD9是铜的调节因子 运输和假设ANKRD9是涉及肠道脂肪的途径的分子整合因子 和铜的运输。拟议的研究计划将检验中心假设，即铜的稳态 和肠细胞中的脂(脂)代谢在功能上是相互联系和共同调节的。特定目标下的研究1 将表征ATP7B的调节机制，并研究肠道铜的储存 舱室已经形成。具体目标2将确定铜和膳食脂肪如何在体内相互影响运输 并阐明了铜依赖形成乳糜粒的机制。具体目标3 将表征ANKRD9在小肠中的功能及其在铜和脂肪偶联中的作用 新陈代谢。这些研究将揭开了解肠道铜生理的新篇章，有助于 更好地了解与铜失衡相关的人类疾病，最终有助于更好地设计 对这些疾病的治疗。

PROJECT SUMMARY Copper (Cu) is essential for the growth, development, and normal function of human organisms. The defects in Cu homeostasis are associated with a broad spectrum of pathologies including Menkes disease, Wilson disease, MEDNIK syndrome, and others. So far, the studies of human Cu homeostasis have focused primarily on the function and regulation of Cu transporters and small Cu carriers. With this program of study, we will begin to learn how mammalian Cu transporters and their regulators work together to modulate the nutrient transport in intestine. The small intestine is responsible for the absorption of all essential nutrients. We discovered that the availability of Cu in enterocytes strongly influenced the abundance of chylomicrons, the primary carriers of dietary fat. We have also identified the fat-responsive protein ANKRD9 as a regulator of Cu transport and hypothesize that ANKRD9 is a molecular integrator of the pathways involved in the intestinal fat and Cu transport. The proposed program of studies will test the central hypothesis that the Cu homeostasis and lipid (fat) metabolism in enterocytes are functionally linked and co-regulated. Studies under Specific Aim 1 will characterize the mechanism of ATP7B regulation and investigate how the intestinal Cu storage compartments are formed. Specific Aim 2 will determine how Cu and dietary fat affect each other transport in enterocytes and elucidate the mechanism behind the Cu-dependent formation of chylomicrons. Specific Aim 3 will characterize the function of ANKRD9 in the small intestine and its role in coupling copper and fat metabolism. The studies will open a new chapter in understanding of intestinal Cu physiology, contribute to better understanding of human disorders associated with Cu misbalance and, ultimately, help to design better treatments for these disorders.