Zinc Importer SLC39A8 and Lung Epithelial Cell Survival

描述（由申请人提供）：锌是细胞所必需的。细胞内锌受到严格的调节，因为锌缺乏和过量可能是有害的。锌转运体控制锌的运动，在维持细胞凋亡、细胞生长和疾病预防之间的平衡中起着至关重要的作用。我们的初步研究结果表明，锌转运蛋白SLC39A8是人肺上皮锌稳态的关键调节因子。我们认为，在炎症应激过程中，锌转运蛋白的表达和功能的调节是锌转运到细胞并启动细胞保护以抵抗诱导死亡的刺激所必需的。我们的具体假设是，锌进口蛋白SLC39A8是主要的转运蛋白，负责增加锌的摄取，并激活肺上皮对炎症应激的先天保护反应。本研究的主要目的是：1)比较SLC39A8在正常和炎症条件下介导的锌摄取，并确定其对原代人肺上皮细胞分化培养中细胞存活的贡献；2)通过位点定向诱变确定SLC39A8蛋白结构和功能与BEAS2B人肺上皮细胞系细胞锌摄取和细胞存活的关系。我们期望我们的结果将为ARDS疾病的易感性和治疗提供新的见解。

DESCRIPTION (provided by applicant): Zinc is essential to cells. Intracellular zinc is tightly regulated as zinc deficiency and excess can be detrimental. Zinc transporters control movement of zinc and have a crucial role in maintaining cellular balance between apoptosis, cell growth, and disease prevention. Our preliminary findings indicate that the zinc transporter, SLC39A8, is a key regulator of zinc homeostasis in the human lung epithelium. We propose that modulation of zinc transporter expression and function during inflammatory stress is required for zinc transport into the cell and initiates cell protection against death-inducing stimuli. Our specific hypothesis is that the zinc importer SLC39A8 is the primary transporter responsible for increased zinc uptake and activation of an innate protective response against inflammatory stress in the lung epithelium. The key aims of this proposal are 1) To compare native SLC39A8-mediated zinc uptake during normal and inflammatory conditions and determine its contribution to cell survival in differentiated cultures of primary human lung epithelia and then 2) determine SLC39A8 protein structure and function with respect to cellular zinc uptake and cell survival in the BEAS2B human lung epithelial cell line via site-directed mutagenesis. We anticipate that our results will provide new insight into ARDS disease susceptibility and treatment.