GENESIS OF DENSE SICKLE CELLS

描述：（改编自研究者摘要） 有三个方面使我们对镰状细胞病有了更好的了解， 病理生理学：1）导致镰状红细胞脱水的运输途径 已被更好地定义和操纵在体内与特定的抑制剂; 2)体内跟踪研究已经阐明了时间依赖性细胞变化 并量化循环中镰状红细胞亚群的行为; 3)使用羟基脲增加HbF的有效疗法已导致 RBC性质和行为的根本变化。 但若干 一些重要问题仍未解决。 很明显有些镰状细胞 在离开骨髓后不久就会脱水，但相对来说， 这些细胞在溶血和血管闭塞中的重要性仍然未知。 每种重要RBC亚型的控制阳离子耗竭途径， 包括由年龄和血红蛋白含量定义的那些，没有被定义。 选择合适的阳离子传输需要这些信息 用于治疗试验的抑制剂。 治疗引起的红细胞变化 与羟基脲是知之甚少，也不清楚是否 HbF的增加是所有临床效应的原因。 在 建议的研究，三种类型的实验将进行：1） RBC亚群密度级分的详细体内分析。 这些 实验将揭示脱水的程度作为一个功能， 年龄和HbF含量，以及这些细胞行为的变化， 治疗的亚型; 2）研究转运途径， 导致年轻和成熟RBC在氧和脱氧条件下脱水， 以及这些途径的活性随治疗的变化：3）在 生物素标记的自体镰状细胞的体内多参数跟踪， 确定RBC亚型的存活和时间依赖性水合变化， 以及有效治疗后发生的变化。 观察到的红细胞 行为将在一个全面的镰刀模型的背景下进行分析 细胞脱水和存活 在该模型中，初始网织红细胞 脱水依赖于KCl共转运途径的活性， K流出，是独立的HbF，而终端阶段的脱水是 镰状化依赖，HbF起重要作用。

DESCRIPTION: (Adapted from investigator's abstract) Recent progress in three areas has led to a better understanding of sickle cell pathophysiology: 1)The transport pathways that cause sickle RBC dehydration have been better defined and manipulated in vivo with specific inhibitors; 2) In vivo tracking studies have illuminated time-dependent cellular changes and quantified the behavior of sickle RBC subpopulations in the circulation; 3) Effective therapy to increase HbF with hydroxyurea has resulted in fundamental changes in RBC properties and behavior. However, a number of important issues remain unresolved. It is clear that some sickle cells become dehydrated soon after leaving the bone marrow, but the relative importance of these cells in hemolysis and vasoocclusion remains unknown. The controlling cation depletion pathways for each important RBC subtype, including those defined by age and hemoglobin content, are not defined. This information is required to select appropriate cation transport inhibitors for therapeutic trials. The RBC changes that result from therapy with hydroxyurea are poorly understood, and it is not clear whether the increase in HbF is responsible for all of the clinical effects. In the proposed research, three types of experiments will be performed: 1) Detailed in vivo analyses of RBC subpopulations in density fractions. These experiments will shed light on the extent of dehydration as a function of age and HbF content, and on changes in the behavior of these cellular subtypes with treatment; 2) Investigations of the transport pathways that lead to dehydration of young and mature RBC under oxy and deoxy conditions, and the changes in the activity of these pathways with treatment: 3) In vivo, multiparametric tracking of biotin-labeled, autologous sickle cells to determine the survival and time-dependent hydration change of RBC subtypes, and the changes that occur after effective treatment. The observed red cell behavior will be analyzed in the context of a comprehensive model of sickle cell dehydration and survival. In this model, initial reticulocyte dehydration is dependent on the activity of the KCI cotransport pathway for K efflux and is independent of HbF, while terminal stages of dehydration are sickling dependent, with HbF playing an important role.