Molecular mechanism underlying the regulation of manganese homeostasis

作为一种必需的营养物质，锰是许多酶的功能所必需的。通过这些酶，锰在人类健康中发挥着重要作用。缺锰会导致生长受阻、骨质疏松、血脂异常、哮喘和认知缺陷。另一方面，锰超载会导致一系列神经和行为缺陷，临床上称为锰中毒。因此，需要严格控制锰的动态平衡，以应对避免缺乏和过载的双重挑战。锰转运蛋白在这一控制中发挥着关键作用。ZIP14(Zrt-and irt-like Protein，Members 14或SLC39A14)是一种新发现的锰进口体。它在小肠和肝脏中高度表达，这两个器官是控制锰代谢的两个主要器官。ZIP14基因功能缺失突变的患者出现严重的儿童期锰超载，表明ZIP14在维持体内锰平衡方面发挥着不可或缺的作用。然而，这种疾病的确切发病机制尚未确定。这项研究的目的是确定ZIP14在调节锰稳态中的功能，并阐明ZIP14突变是如何导致锰毒性的。本研究从两个水平上对ZIP14的S功能进行了研究：一是调控细胞内锰转运的功能；二是平衡全身锰稳态的功能。我们将结合使用细胞分析和转基因小鼠模型来确定决定ZIP14‘S功能的新因素，并探讨新发现在疾病生物学中的生理学意义。我们提出的研究将提供一个更全面的理解如何控制锰的动态平衡，以及如何在缺乏功能性ZIP14的个体中诱导锰超载。该项目将在确定新的治疗靶点和开发有效的预防策略方面具有巨大的潜力，从而将对患者的不利健康影响降至最低。

As an essential nutrient, manganese is required for the function of numerous enzymes. Through these enzymes, manganese plays important roles in human health. Manganese deficiency leads to impaired growth, osteoporosis, dyslipidemia, asthma, and cognitive defects. Manganese overload, on the other hand, produces a spectrum of neurological and behavioral defects, clinically known as manganism. Therefore, manganese homeostasis needs to be tightly controlled to meet the dual challenge of avoiding deficiency and overload. Manganese transporters play critical roles in this control. ZIP14 (Zrt- and Irt-like protein, member 14, or SLC39A14) is a newly identified manganese importer. It is highly expressed in the small intestine and liver, that are the two major organs involved in the control of manganese metabolism. Patients with loss-of-function mutations in ZIP14 developed severe childhood-onset manganese overload, indicating an indispensable role for ZIP14 in maintaining body manganese homeostasis. However, the precise mechanism of this disease has not been determined. The goal of this proposed research is to determine the function of ZIP14 in regulating manganese homeostasis and to elucidate how ZIP14 mutations lead to manganese toxicity. This application focuses on ZIP14’s function at two levels: its role in regulating cellular manganese transport and its function in balancing whole-body manganese homeostasis. We will use a combination of cell assays and genetically modified mouse models to identify new factors that determine ZIP14’s function and to investigate the physiological significance of new findings in disease biology. Our proposed research will provide a more comprehensive understanding of how manganese homeostasis is controlled and how manganese overload is induced in individuals lacking functional ZIP14. This project will have great potential for identifying novel therapeutic targets and developing effective prevention strategies that would minimize adverse health impacts occurred in patients