Molecular mechanism underlying the regulation of manganese homeostasis

作为一种必需的营养素，锰是许多酶功能所必需的。通过这些酶，锰在人类健康中起着重要作用。锰缺乏会导致生长障碍、骨质疏松症、血脂异常、哮喘和认知缺陷。另一方面，锰超载会产生一系列神经和行为缺陷，临床上称为锰中毒。因此，锰稳态需要严格控制，以满足避免缺乏和过载的双重挑战。锰转运蛋白在这种控制中起着关键作用。ZIP 14（Zrt-and Irt-like protein，member 14，SLC 39 A14）是一种新发现的锰输入蛋白。它在小肠和肝脏中高度表达，这是参与锰代谢控制的两个主要器官。ZIP 14功能缺失突变的患者发生了严重的儿童期锰超载，这表明ZIP 14在维持体内锰稳态方面具有不可或缺的作用。然而，这种疾病的确切机制尚未确定。这项研究的目的是确定ZIP 14在调节锰稳态中的功能，并阐明ZIP 14突变如何导致锰毒性。本申请集中于ZIP 14在两个水平上的功能：其在调节细胞锰转运中的作用和其在平衡全身锰稳态中的功能。我们将使用细胞测定和转基因小鼠模型的组合来确定决定ZIP 14功能的新因素，并研究疾病生物学新发现的生理意义。我们提出的研究将提供一个更全面的了解锰稳态是如何控制的，以及锰超载是如何在缺乏功能性ZIP 14的个体中诱导的。该项目将具有很大的潜力，以确定新的治疗靶点和制定有效的预防策略，将最大限度地减少对患者健康的不良影响

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