SLC39A13（ZIP13）突变引起一种人类胶原疾病埃勒斯-当洛斯综合征（SCD-EDS），其发病机理尚不明确。现有的ZIP13锌离子转运理论也不足以解释其发病机制，因为在胶原合成和分泌过程中并无锌离子参与。但研究发现果蝇ZIP13可负责铁离子由胞质向ER/Golgi转运。这一发现可对该疾病中的胶原缺陷做出合理解释：位于ER的胶原修饰酶需要铁离子作为辅基发挥作用，铁离子缺乏将影响胶原交联与成熟。本课题将参照果蝇模型的研究结果，以哺乳细胞和Zip13敲除小鼠为实验模型，探索ZIP13在哺乳细胞铁代谢中的作用：即回答ZIP13在哺乳类细胞中是否也介导铁离子从胞质向ER/Golgi转运？其突变是否通过抑制铁离子的转运，导致胶原修饰酶因无法获得辅基而失活，从而抑制胶原的合成和分泌？该项目的创新性研究结果可能对揭示该疾病的病理机制，发掘有效的治疗方法以及进一步深入了解哺乳细胞铁代谢提供关键依据。

Mutations in SLC39A13 (ZIP13) cause a human collagen disease called the Spondylocheiro Dysplastic form of Ehlers-Danlos Syndrome (SCD-EDS). The pathogenesis of this disease is still unresolved. Moreover, the existing ZIP13 zinc ion transport theory is unable to sufficiently explain the pathogenesis, because zinc ion is not known to participate in any process of collagen synthesis and secretion. However, the research with drosophila has surprisingly indicated that drosophila ZIP13 is an iron ion transporter, responsible for moving iron ion from the cytoplasm to ER/Golgi. This finding could satisfactorily explain the etiology of SCD-EDS: iron is required as a cofactor for ER-resident collagen cross-linking enzymes, so that iron deficiency would affect collagen crosslinking and maturation. On the basis of earlier finding made in drosophila, this project will use mammalian cells and Zip13-knockout mice as experimental models to explore the possible roles of ZIP13 in iron metabolism in mammalian cells. We intend to answer these questions: Does ZIP13 also mediate the transport of iron ion from the cytoplasm to ER/Golgi in mammalian cells? Does the ZIP13 mutation prevent the transfer of iron ion from the cytoplasm to ER/Golgi, causing activity loss of the collagen-modifying enzymes located in ER, thereby affecting collagen maturation and secretion? These creative findings from this project are anticipated to provide insights into the pathological mechanism of SCD-EDS, to reveal novel therapeutic strategy and to further our understanding of iron metabolism in mammalian cells.