Differentiation of Granulocytes and Macrophages

粒细胞和巨噬细胞的分化

• 批准号: 8708766
• 负责人: DONALD METCALF
• 金额: $ 22.33万
• 依托单位: WALTER AND ELIZA HALL INST MEDICAL RES
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-03-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8708766
• 关键词: Anemia; Autoimmunity; Biochemical; Biological; Blood Cells; CSF3 gene; Cells; Cellular biology; Chemotherapy-Oncologic Procedure; Cytokine Inducible SH2-Containing Protein; Cytokine Receptors; Cytokine Signaling; Development; Disease; Family member; Goals; Hematopoietic; Hematopoietic Neoplasms; Host Defense; Individual; Infection; Inflammation; Inflammatory; Instruction; Interleukin-6; Intervention; Leukocytes; Malignant Neoplasms; Molecular; Myeloid Progenitor Cells; Outcome; Patients; Physiological; Play; Production; Proteins; Recovery; Regulation; Role; Signal Transduction; Signal Transduction Pathway; Signaling Protein; Structure; Suppressor of Cytokine Signaling Family Protein; Tertiary Protein Structure; base; biological systems; cytokine; embryonic stem cell; granulocyte; in vivo; macrophage; mouse model; neutrophil; novel; prevent; receptor; stem cell biology; tool

Cytokines are secreted regulators that control the production, maturation and functional activation of blood cells that are essential for hemostasia and host defense from infection. These beneficial actions of cytokines have been harnessed clinically, for example the use of G-CSF to promote recovery of white blood cells in patients receiving cancer chemotherapy, or EPO to treat anemia. In addition, deregulation of cytokines, their receptors or intracellular signal transduction pathways is associated with autoimmunity and cancer. The importance of negative regulation of cytokine signaling cascades has come clearly into focus with our identification and characterization of the family of Suppressors of Cytokine Signaling (SOCS) proteins. Our long-term objective is to identify the specific cytokines regulated by individual SOCS proteins and the cells and biological systems dependent on SOCS regulation. We seek to define the biochemical basis of SOCS action via elucidation of the structures of, and physical interactions between, SOCS proteins and the signaling machinery and to define the disease contexts in which manipulation of SOCS proteins may prove clinically beneficial. Our focus here is on S0CS3, the key negative regulator of G-CSF and IL-6 that is required to prevent spontaneous inflammatory disease. Applying a multidlsciplinary approach employing biochemical and structural biological tools, cell biology and genetically modified mouse models, our major goals are: defining the specific roles of S0CS3 in relevant mouse models of inflammation and hematopoietic malignancy, understanding the shared or overlapping physiological roles of S0CS3 with other SOCS family members, and defining the functions of protein domains within the overall actions of S0CS3, along with discovery of novel protein targets of S0CS3 action. RELEVANCE (See instructions): Successful outcomes will provide new strategies for intervention in cytokine-related diseases, particularly cancer and inflammation.

细胞因子是控制血液产生、成熟和功能活化的分泌调节因子 止血和宿主防御感染所必需的细胞。细胞因子的这些有益作用 已经在临床上得到利用，例如，使用G-CSF来促进白色血细胞的恢复， 接受癌症化疗或EPO治疗贫血的患者。此外，细胞因子的失调， 受体或细胞内信号转导途径与自身免疫和癌症有关。的 细胞因子信号级联负调节的重要性已经清楚地成为我们关注的焦点。 细胞因子信号传导抑制因子（SOCS）蛋白家族的鉴定和表征。我们 长期目标是鉴定由单个SOCS蛋白和细胞调节的特异性细胞因子， 以及依赖于SOCS调节的生物系统。我们试图定义SOCS的生物化学基础 通过阐明SOCS蛋白质的结构和它们之间的物理相互作用， 信号机制，并确定SOCS蛋白的操纵可能证明的疾病背景 临床有益。我们的重点是S 0 CS3，它是G-CSF和IL-6的关键负调节因子， 以防止自发性炎症性疾病。应用多学科方法， 我们的专业是生化和结构生物学工具、细胞生物学和遗传修饰小鼠模型 目的是：确定SOCS 3在炎症和造血相关小鼠模型中的特定作用， 恶性肿瘤，了解S 0 CS3与其他SOCS家族共享或重叠的生理作用 成员，并在SOCS 3的整体作用中定义蛋白质结构域的功能，沿着 发现S 0 CS3作用的新蛋白质靶标。 相关性（参见说明）： 成功的结果将提供新的战略，干预与毒品有关的疾病，特别是 癌症和炎症。