Zinc Importer SLC39A8 and Lung Epithelial Cell Survival

说明(申请人提供)：锌是细胞所必需的。细胞内的锌受到严格的调控，因为缺锌和过量锌可能是有害的。锌转运蛋白控制锌的运动，在维持细胞凋亡、细胞生长和疾病预防之间的平衡方面起着至关重要的作用。我们的初步发现表明，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，炎症应激期间锌转运蛋白的表达和功能的调节是锌转运到细胞内并启动对死亡诱导刺激的细胞保护所必需的。我们的具体假设是，锌进口体SLC39A8是主要的转运体，负责增加肺上皮对锌的摄取和激活针对炎症应激的天然保护性反应。本研究的主要目的是：1)比较正常和炎症条件下天然的SLC39A8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影响；2)通过定点突变，确定SLC39A8蛋白的结构和功能与BEAS2B人肺上皮细胞锌摄取和细胞存活的关系。我们预计，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.