Mechanism for copper-deficiency mediated neutropenia

缺铜介导的中性粒细胞减少症的机制

基本信息

批准号：
8504553
负责人：
Dennis J Thiele
金额：
$ 19.63万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-15 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8504553
关键词：
Address Alzheimer&apos 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

项目摘要

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（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的必不可少的痕量要素。 CU缺乏会导致严重的中性粒细胞减少症，这是吞噬细胞的耗竭，代表细菌和真菌感染中的第一道防线，从而使患者易受威胁生命的感染疾病。癌症患者的放射治疗也是由于抗生素，镇静剂和抗炎药以及先天性或先天性或特发性疾病形式而发生的中性粒细胞减少症。尽管许多进行CU运输，分布和利用的组件都是良好的，但哺乳动物感知Cu缺乏的分子机制，以及这些机制参与中性粒细胞发育中的介入，代表了我们知识的关键差距。我们已经发现，需要的关键转录抑制剂蛋白需要对于嗜中性粒细胞的发育，GFI1因响应遗传性或饮食中的CU缺乏而严重不稳定。在此提案中，我们概述了两个具体目的，该目标将（1）确定CU缺乏导致GFI1降解和中性粒细胞减少症的关键分子途径，以及（2）检验的假设，即对CU水平的饮食操纵可以改善中性粒细胞减少。该提案的创新成分包括：（1）建立CU缺乏诱导的中性粒细胞减少症的机理基础（2）阐明了通过蛋白质降解来调节先天性免疫细胞分化的新型分子机制，并确定（3）通过补充Cu补充中性粒细胞减少的潜力。综上所述，该提案中概述的研究可能会发现新颖的CU信号通路，这些cu信号通路调节了关键的先天免疫细胞的发展，这是针对细菌和真菌感染的第一道防线。