Mechanism for copper-deficiency mediated neutropenia

描述（由申请人提供）：铜（Cu）是正常生长和发育以及先天免疫系统的适当分化和功能所必需的微量元素。铜缺乏会导致严重的中性粒细胞减少症，这是代表细菌和真菌感染的第一道防线的吞噬细胞的耗竭，从而使患者容易患上危及生命的传染病。中性粒细胞减少症也作为癌症患者中放射治疗的结果，响应于药物如抗生素、镇静剂和抗炎剂，以及作为疾病的先天性或特发性形式发生。虽然进行铜的运输，分布和利用的许多组件是完善的，哺乳动物的分子机制，其中铜缺乏症的感觉，并参与这些机制在中性粒细胞的发展，代表了我们的知识的一个关键差距。我们已经发现髓样前体细胞中的一种关键转录抑制蛋白， 对于嗜中性粒细胞的发育，Gfi 1在遗传或饮食强加的铜缺乏时严重不稳定。在这项提案中，我们概述了两个具体的目标，将（1）确定铜缺乏导致Gfi 1降解和中性粒细胞减少症的关键分子途径和（2）测试的假设，饮食控制铜水平可以改善中性粒细胞减少症。该提案的创新部分包括：（1）建立铜缺乏诱导的中性粒细胞减少症的机制基础;（2）阐明铜通过蛋白质降解调节先天免疫细胞分化的新分子机制;（3）确定通过补充铜补救中性粒细胞减少症的潜力。总之，本提案中概述的研究有可能发现新的Cu信号通路，这些通路调节关键先天免疫细胞的发育，这些细胞是抵御细菌和真菌感染的第一道防线。

DESCRIPTION (provided by applicant): Copper (Cu) is an essential trace element for normal growth and development and for the proper differentiation and function of the innate immune system. Cu deficiency causes severe neutropenia, a depletion of the phagocytic cells that represent the first line of defense in bacterial and fungal infections, thereby rendering patients susceptible to life-threatening infectious disease. Neutropenia also occurs as a consequence of radiation therapy in cancer patients, in response to drugs such as antibiotics, sedatives and anti-inflammatory agents, and as congenital or idiopathic forms of the disease. While many of the components that carry out Cu transport, distribution and utilization are well-established, the molecular mechanisms by which mammals sense Cu deficiency, and the involvement of these mechanisms in neutrophil development, represent a critical gap in our knowledge. We have discovered that a key transcriptional repressor protein in myeloid precursor cells that is required for neutrophil development, Gfi1, is severely destabilized in response to a genetic- or dietary-imposed Cu deficiency. In this proposal we outline two specific aims that will (1) identify key molecular pathways by which Cu deficiency leads to Gfi1 degradation and neutropenia and (2) test the hypothesis that dietary manipulation of Cu levels can ameliorate neutropenia. The innovative components of this proposal include: (1) establishment of a mechanistic basis for Cu deficiency- induced neutropenia (2) the elucidation of novel molecular mechanisms for Cu regulation of innate immune cell differentiation via protein degradation and (3) ascertain the potential for remediation of neutropenia by Cu supplementation. Taken together, the studies outlined in this proposal have the potential to discover novel Cu signaling pathways that modulate the development of key innate immune cells that are the first line of defense against bacterial and fungal infection.