Mechanism for copper-deficiency mediated neutropenia

缺铜介导的中性粒细胞减少症的机制

• 批准号: 8605173
• 负责人: Dennis J Thiele
• 金额: $ 23.55万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-15 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8605173
• 关键词: Address; Alzheimer' s Disease; Anti-Inflammatory Agents; Antibiotics; Bacterial Infections; Biochemical; Biogenesis; Bone Marrow; Cancer Patient; Cardiomyopathies; Cell Differentiation process; Cell Line; Cell physiology; Cells; Communicable Diseases; Copper; Data; Defect; Development; Diet; Dietary Component; Dietary Copper; Disease; Employee Strikes; Gene Expression; Gene Mutation; Gene Targeting; Genetic; Growth and Development function; Health; Human; Immune; Immune system; Infection; Knockout Mice; Knowledge; Leukocytes; Life; Light; Link; Mammals; Mediating; Metabolic Diseases; Molecular; Mus; Mutation; Mycoses; Myelogenous; Myeloid Progenitor Cells; Neutropenia; Pathology; Pathway interactions; Patients; Peripheral Nervous System Diseases; Phagocytes; Pharmaceutical Preparations; Proteasome Inhibition; Proteins; Proteolysis; Radiation therapy; Regulation; Reporting; Repression; Repressor Proteins; Research; Role; Signal Pathway; Site; Spleen; Supplementation; Testing; Therapeutic; Trace Elements; Transcription Repressor/Corepressor; Work; base; design; human disease; hypocupremia; in vivo; innovation; microbial; mouse model; neutrophil; novel; precursor cell; prevent; protein degradation; public health relevance; remediation; research study; response; sedative

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.

说明(申请人提供)：铜(铜)是正常生长和发育以及天然免疫系统正常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，吞噬细胞是细菌和真菌感染的第一道防线，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是癌症患者接受放射治疗、抗生素、镇静剂和抗炎药等药物反应的结果，也是先天性或特发性疾病的结果。虽然许多进行铜的运输、分配和利用的成分都是已知的，但哺乳动物感受到铜缺乏的分子机制，以及这些机制参与中性粒细胞发育的机制，在我们的知识中代表着一个关键的缺口。我们已经发现，髓系前体细胞中需要一种关键的转录抑制蛋白 对于中性粒细胞的发育，Gfi1是严重不稳定的，以响应遗传或饮食造成的铜缺乏。在这项建议中，我们概述了两个具体的目标，这将(1)确定铜缺乏导致Gfi1降解和中性粒细胞减少的关键分子途径，以及(2)检验饮食中控制铜水平可以改善中性粒细胞减少症的假设。这一建议的创新部分包括：(1)建立铜缺乏引起的中性粒细胞减少的机制基础(2)阐明铜通过蛋白质降解调节天然免疫细胞分化的新的分子机制，以及(3)确定通过补充铜来修复中性粒细胞减少的可能性。综上所述，这项建议中概述的研究有可能发现新的铜信号通路，这些通路调节关键的先天性免疫细胞的发育，这些细胞是抵御细菌和真菌感染的第一道防线。