GENESIS OF DENSE SICKLE CELLS

描述：(改编自调查人员摘要)最近的进展 三个方面使人们对镰状细胞有了更好的理解 病理生理学：1)引起镰状红细胞脱水的运输途径 已经在体内用特定的抑制物更好地定义和操纵； 2)活体跟踪研究揭示了依赖时间的细胞变化 并量化镰状红细胞亚群在循环中的行为； 3)羟基尿素增加HbF的有效治疗 红细胞性质和行为的根本性变化。然而，一些人 重要问题仍未得到解决。很明显，一些镰状细胞 在离开骨髓后不久就会脱水，但相对的 这些细胞在溶血和血管闭塞中的重要性仍不清楚。 控制每个重要RBC亚型的阳离子消耗途径， 包括由年龄和血红蛋白含量定义的那些，没有定义。 此信息是选择适当的阳离子传输所必需的 用于治疗试验的抑制剂。治疗引起的红细胞变化 对羟基脲的了解很少，也不清楚是否 HbF的增加是所有临床效果的原因。在 建议的研究，将进行三种类型的实验：1) 对密度分数中的红细胞亚群进行了详细的活体分析。这些 实验将阐明脱水的程度作为 年龄和HbF含量，以及这些细胞行为的变化 亚型与治疗；2)运输途径的调查 导致年轻和成熟的红细胞在缺氧和脱氧条件下脱水， 治疗后这些通路活性的变化：3)在 活体、多参数跟踪生物素标记的自体镰状细胞以 确定RBC亚型的存活率和随时间的水化变化， 以及有效治疗后发生的变化。观察到的红细胞 行为将在镰刀的综合模型的背景下进行分析 细胞脱水和存活。在这个模型中，初始网织红细胞 脱水依赖于KCI共转运途径的活性 K外流，不依赖于HBF，而脱水的终末阶段是 镰状依赖，其中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.