THE BIOLOGIC SIGNIFICANCE OF PLATELET HETEROGENEITY

血小板在生理和功能方面是异质性的 特性. 本项目的总体目标是确定 血小板异质性的生物学意义。 它将考验 假设血小板异质性部分由年龄决定， 外周循环 这种假设的衰老过程 由于血小板的先天异质性和细胞器的选择性损失 导致密度降低。 该假设将通过 四个具体目标。 1.老年和年轻血小板组将在鼠模型中产生，使用 Sr 89骨髓消融或Co 60外照射。 密度 这些年龄依赖性队列的分布将根据等摩尔浓度进行分析。 密度梯度以确定血小板年龄对血小板的影响 密度和平均血小板体积（MPV）。 骨髓和脾 巨核细胞集落形成能力（Meg-CFC），巨核细胞DNA含量， 和巨核细胞成熟阶段进行研究，以评估 每种血小板生成成分对血小板异质性的贡献。 2.将使用刺激的鼠红细胞生成模型来研究 血小板生成改变对血小板密度分布，MPV， 巨核细胞倍性分布、巨核细胞成熟和Meg-CFC。 该模型将利用急性和慢性免疫性血小板减少症、急性血小板减少症和慢性血小板减少症。 出血、5-氟尿嘧啶和环磷酰胺干扰血小板生成。 3.将使用两种人类血小板产生模型来检查 新产生的人血小板的密度分布。 患者研究 在自身免疫性血小板减少症的恢复期， 年轻的血小板队列在扰动状态;和密度分布 阿司匹林抑制恢复期血小板血栓素B_2合成 将提供新释放的血小板的未扰动标记队列， 检查血小板年龄和密度之间的关系。 4.不同密度血小板的细胞器含量 测定了 如果衰老过程中选择性的细胞器丢失或分泌改变了 密度，那么那些丢失的成分的水平应该 下降，而那些没有失去的水平应保持不变 常数 线粒体，溶酶体， 过氧化物酶体、致密体、α颗粒和不同的细胞质 将对血小板密度组群进行定量以检验这一命题。

Platelets are heterogeneous with respect to both physical and functional properties. The overall objective of this project is to deterine the biologic significance of platelet heterogeneity. It will test the hypothesis that platelet heterogeneity is in part determined by aging in the peripheral circulation. This postulate aging process is superimposed upon inborn platelet heterogeneity and is due to selective organelle loss resulting in decreasing density. The hypothesis will be tested through the use of four specific aims. 1. Old and young platelet cohorts will be produced in a murine model using either Sr89 bone marrow ablation or Co60 external irradiation. The density distribution of these age dependent cohorts will be analyzed on isomolar density gradients to determine the effect of platelet age on platelet density and mean platelet volume (MPV). Bone marrow and spleen megakaryocyte colony forming capacity (Meg-CFC), megakaryocyte DNA content, and megakaryocyte maturation stage will be studied to evaluate the contribution of each thrombopoietic component to platelet heterogeneity. 2. A stimulated murine rhrombopoiesis model will be used to study the effects of altered thrombopoiesis on platelet density distribution, MPV, megakaryocyte ploidy distribution, megakaryocyte maturation, and Meg-CFC. The model will utilize acute and chronic immune thrombocytopenia, acute hemorrhage, 5-fluorouracil and cytoxan to perturb platelet production. 3. Two models of human platelet production will be used to examine the density distribution of newly produced human platelets. Study of patients during the recovery phase of autoimmune thrombocytopenia will provide a young platelet cohort in a perturbed state; and the density distribution of platelet thromboxane B2 synthesis during recovery from aspirin inhibition will provide an unperturbed labelled cohort of newly released platelets to examine the relationship between platelet age and density. 4. The organelle content of platelets of various densities will be measured. If selective organelle loss or secretion during aging alters density, then the levels of those constitutents which are lost should decline while the levels of those which are not lost should remain constant. Representative constituents of mitochondria, lysosome, peroxisomes, dense bodies, alpha granules, and cytoplasm of different platelet density cohorts will be quantitated to test this proposition.