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.

描述（申请人提供）：铜（Cu）是正常生长发育和先天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症，即作为细菌和真菌感染第一道防线的吞噬细胞的消耗，从而使患者易患危及生命的传染病。中性粒细胞减少症也发生在癌症患者放射治疗的结果中，作为对抗生素、镇静剂和抗炎剂等药物的反应，以及作为先天性或特发性疾病形式。虽然许多进行铜运输、分布和利用的成分已经建立，但哺乳动物感知铜缺乏的分子机制，以及这些机制在中性粒细胞发育中的参与，在我们的知识中代表了一个关键的空白。我们发现骨髓前体细胞中需要一种关键的转录抑制蛋白