CHARACTERIZATION OF CELL DEFECTS IN CYCLIC HEMATOPOIESIS

循环造血过程中细胞缺陷的表征

• 批准号: 3334998
• 负责人: JIMMY B JONES
• 金额: $ 15.03万
• 依托单位: UNIVERSITY OF TENNESSEE KNOXVILLE
• 依托单位国家: 美国
• 财政年份: 1976
• 资助国家: 美国
• 起止时间: 1976-12-01 至 1988-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3334998
• 关键词: 3'5' cyclic nucleotide phosphodiesterase; adenylate cyclase; animal colony; arachidonate; bone marrow transplantation; calcium; cell growth regulation; clone cells; computer simulation; congenital blood disorder; cyclic AMP; electron microscopy; erythropoiesis; granule; hematopoiesis; hematopoietic stem cells; high performance liquid chromatography; human subject; ionophores; leukocyte activation /transformation; leukopenia; leukopoiesis; lipid metabolism; lymphocyte; mathematical model; neutrophil; peptides; phorbols; phosphatidylinositols; phosphorylation; platelet aggregation; platelets; prostaglandins; superoxides

Cyclic hematopoiesis (CH) in man and the dog is a genetic disease characterized by periodic fluctuations in blood cells, particularly neutrophils. Many studies indicate that the fluctuations in circulating blood cells result from cyclic proliferation of the hematologic stem cell. A defect of unknown origin in extracellular to intracellular membrane signal transduction has recently been identified in platelets from CH dogs and human patients with CH disease, based on defective platelet aggregation to collagen and platelet activating factor, (PAF) and normal thromboxane production. The broad aims of these studies are to identify the specific cellular defects in human and canine CH platelets, determine if similar defects are present in neutrophils and lymphocytes and relate the defect(s) to cyclic cell proliferation. The majority of the specific aims are designed to determine if defects exist in the second messenger system of all blood cells of CH dogs and humans. Mathematical modeling of erythropoiesis and granulopoiesis in CH dogs will be used to further examine why granulopoiesis has stable cycles and erythropoiesis is mildly affected. The long term objective is to understand exactly how the cycles of hematopoiesis are brought about through alterations in controls of cell division and interactions among populations of cells. The following methodology will be used to achieve the specific aims: 1) Characterize the platelet second messenger defect by measuring cAMP concentrations and adenylate cyclase activity, cyclic nucleotide phosphodiesterase activity, calmodulin, calcium mobilization, inositol phospholipid metabolism, protein phosphorylations and platelet granule contents in CH and normal platelets. 2) Comparisons of CH and normal neutrophils response to secretogogues such as FMLP, PAF and A23187 in terms of threshold sensitivity, aggregation, receptor-mediated arachidonic acid release, degranulation and superoxide formation. 3) Compare normal and CH lymphocyte responses to mitogenic stimulation. 4) Compare proliferation activity of CH and normal bone marrow cultures (Dextersystem) to known growth modulators, and 5) Computer model erythropoiesis and granulopoiesis of normal and CH dogs. Identification of the biochemical defect(s) responsible for CH disease should provide a better understanding of the comparable blood disorder of humans. These studies cross multiple disciplines of biology and medicine and should contribute important new information on cell regulatory mechanisms in hematopoietic proliferative diseases.

人类和狗的环状造血（CH）是一种遗传疾病 以血细胞的周期性波动为特征，特别是 中性粒细胞。 许多研究表明循环中的波动 血细胞是由血液学干细胞的环状增殖引起的。 细胞外到细胞内膜中未知来源的缺陷 最近在CH狗的血小板中发现了信号转导 和患有CH疾病的人类患者，基于缺陷的血小板聚集 到胶原蛋白和血小板激活因子（PAF）和正常血栓烷 生产。 这些研究的广泛目的是确定特定的细胞 人类和犬Ch血小板中的缺陷，确定相似的缺陷是否为 存在于中性粒细胞和淋巴细胞中，并将缺陷与环状相关 细胞增殖。 大多数特定目标旨在 确定在所有血液的第二信使系统中是否存在缺陷 CH狗和人类的细胞。 红细胞生成和数学建模 CH狗中的粒状虫素将用于进一步研究为什么 颗粒具有稳定的周期，红细胞生成受到轻微影响。 长期目标是准确了解如何循环 造血是通过改变细胞的控制而引起的 细胞种群之间的分裂和相互作用。 以下方法将用于实现特定目的：1） 通过测量营地来表征血小板第二信使缺陷 浓度和腺苷酸环化酶活性，环状核苷酸 磷酸二酯酶活性，钙调蛋白，钙动员，肌醇 磷脂代谢，蛋白质磷酸化和血小板颗粒 CH和正常血小板中的内容。 2）CH和正常的比较 中性粒细胞对诸如FMLP，PAF和A23187等秘密的反应术语 阈值灵敏度，聚集，受体介导的花生四烯酸 释放，脱粒和超氧化物形成。 3）比较正常和CH 淋巴细胞对有丝分裂刺激的反应。 4）比较增殖 CH和正常骨髓培养物（敏感性系统）的活性 生长调节器以及5）计算机模型红细胞生成和粒状剂 正常和CH狗。 识别负责CH疾病的生化缺陷 应该更好地了解 人类。 这些研究跨越了生物学和医学的多个学科 并应为细胞调节的重要新信息提供重要的新信息 造血增殖性疾病的机制。