CHARACTERIZATION OF CELL DEFECTS IN CYCLIC HEMATOPOIESIS

人和狗的循环性造血是一种遗传性疾病 以血细胞的周期性波动为特征的，尤其是 中性粒细胞。许多研究表明，循环中的波动 血细胞是血液干细胞循环增殖的结果。 一种原因不明的细胞外膜到胞内膜缺陷 最近在CH犬的血小板中发现了信号转导 和人类CH病患者，基于血小板聚集缺陷 对胶原和血小板活化因子(PAF)和正常血栓素的影响 制作。 这些研究的主要目的是识别特定的细胞 人和狗的CH血小板的缺陷，决定了类似的缺陷是否 存在于中性粒细胞和淋巴细胞中，并将这种缺陷(S)与循环 细胞增殖。大多数具体目标都是为了 确定所有血液的第二信使系统是否存在缺陷 CH犬和人的细胞。红细胞生成和红细胞生成的数学模型 CH犬的粒细胞生成将被用来进一步研究为什么 粒细胞生成有稳定的周期，红细胞生成受到轻微影响。 我们的长期目标是准确地理解 造血是通过改变细胞的控制来实现的。 细胞群体间的分裂和相互作用。 将使用以下方法来实现具体目标：1) 用cAMP测定鉴定血小板第二信使缺陷 浓度和腺苷环化酶活性，环核苷酸 磷酸二酯酶活性、钙调蛋白、钙动员、肌醇 磷脂代谢、蛋白质磷酸化与血小板颗粒 CH和正常血小板中的含量。2)CH与Normal的比较 中性粒细胞对FMLP、PAF和A23187等分泌性抗原的反应 阈值敏感性、聚集性、受体介导的花生四烯酸 释放、脱颗粒和形成超氧化物。3)比较Normal和CH 淋巴细胞对有丝分裂刺激的反应。4)比较扩散 已知CH和正常骨髓培养(Dextersystem)的活性 生长调节剂，以及5)计算机模型红细胞生成和粒细胞生成 正常犬和CH犬。 引起CH病的生化缺陷(S)的鉴定 应该能让我们更好地理解类似的血液疾病 人类。这些研究涉及生物学和医学的多个学科。 并应在细胞调控方面提供重要的新信息 造血增生性疾病的机制。

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.