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CELLULAR DETERMINANTS OF RED CELL SICKLING

CELLULAR DETERMINANTS OF RED CELL SICKLING
红细胞镰状化的细胞决定因素
批准号:
6109386
负责人:
Carlo Brugnara
金额:
$26.66万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
1999
资助国家:
美国
项目状态:
已结题
起止时间:
1999-04-01 至 2000-03-31

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中文摘要
翻译
HB S聚合和镰刀是中国 镰状细胞病的病理生理学。这些患者的血液是 以脱水、致密的红细胞存在为特征的,具有 升高的血红蛋白S浓度。由于血红蛋白升高,S 浓度显著提高了Hb-S聚合物的形成速率,提高了Hb-Hb 细胞病变的程度,一种可能的治疗方法是基于 通过特定的运输阻断来防止细胞脱水 涉及到的路径。两条钾外流途径在细胞内起主要作用 脱水,即K-C共转运系统和钙激活 (Gardos)K频道。钾-氯共转运系统的分子同一性和 钙激活(Gardos)钾通道。K-Cl的分子同一性 共转运蛋白(HKCC1)最近被阐明。虽然红系 Gardo通道尚未被克隆,几个相关的钙门控K通道 大电导(BK)和小电导(SK)已被克隆。研究项目: 体外镰状红细胞和体内转基因SAD小鼠和 纯合子HB S(Ss)病的患者已显示出脱水 镰状红细胞可以通过对Gardos的特定封锁而减少 经咪唑类抗真菌克霉唑(CLT)或特异性 提高红细胞微克数阻断钾-氯共转运 通过饮食微克补充剂的含量。我们的研究目标将是 以下内容: 1)Gardos通道和K-Cl共转运在镰刀脱水中的作用 红细胞和网织红细胞;2)人类的分子特征 和小鼠红细胞钾-氯联合转运蛋白:这两者的主要关注点 特定的目标是分子和生物物理特征的 Gardos通道和K-Cl共转运体,特别强调这些 可以在小鼠身上和在 人类,正如我们正在进行的临床和小鼠研究所表明的那样。3)效果 钾转运通路对红细胞水化状态的体内调控 关于转基因镰刀鼠的镰刀病表型:我们将重点关注 小鼠镰状细胞病的临床表现 模型可以通过调节两者中的任何一个的活动来影响 运输通道。氯化钾的药理阻断作用 将研究CoTransport或Gardos信道,以及上行链路的影响。 和K-Cl共转运的下调 转化为具有高或低K-Cl共转运活性的菌株或通过遗传 K-Cl共转运基因或其调控因子的操纵。 这些研究旨在深入了解细胞的基础 镰状细胞中的脱水,最终目标是开发新的 镰状细胞病患者的治疗选择。它们代表着 产学研合作的逻辑延伸与成功 由本供资周期支持的研究。
英文摘要
Hb S polymerization and sickling are the central events in the pathophysiology of sickle cell disease. The blood of these patients is characterized by the presence of dehydrated, dense erythrocytes, with an elevated hemoglobin S concentration. Since increases in hemoglobin S concentration markedly increase the rate of Hb S polymer formation and the extent of cell sickling, a possible therapeutic approach is based on the prevention of cell dehydration by specific blockade of the transport pathways involved. Two K efflux pathways play a major role in cell dehydration, namely the K-C cotransport system and the Ca-activated (Gardos) K channel. The molecular identity of K-Cl cotransport system and the Ca-activated (Gardos) K channel. The molecular identity of K-Cl cotransport (hKCC1) has been recently elucidated. Although the erythroid Gardo channel has not been yet cloned, several related Ca-gated K channels of large (BK) and small (SK) conductance have been cloned. Studies in vitro in sickle erythrocytes and in vivo in transgenic SAD mice and patients with homozygous Hb S (ss) disease have shown that dehydration of sickle erythrocytes can be diminished by specific blockade of the Gardos channel by the imidazole antimycotic clotrimazole (CLT) or by specific blockade of K-Cl cotransport by increasing the erythrocyte microgram content via dietary microgram supplements. Our studies will be aimed at the following: 1) Role of Gardos channel and K-Cl cotransport in dehydration of sickle erythrocytes and reticulocytes; 2) Molecular characterization of the human and mouse erythrocyte K-Cl cotransporters: The major focus of these two specific aims is the molecular and biophysical characterization of the Gardos channel and the K-Cl cotransporter, with special emphasis on those properties which can be therapeutically manipulated in mouse and in humans, as shown in our ongoing clinical and mouse studies. 3) The effect of in vivo modulation of K transport pathways on red cell hydration state and on sickle disease phenotype in transgenic sickle mice: We will focus on how the clinical manifestation of sickle cell disease in the mouse model can be affected by modulating the activity of either one of the two transport pathways. The effect of pharmacological blockade of K-Cl cotransport or Gardos channel will be studied, as ell as the effect of up- and down-modulation of K-Cl cotransport by either breeding sickle mice into strains with high or low K-Cl cotransport activity or by genetic manipulation of K-Cl cotransport gene or its regulators. These studies are designed to gain insight into the bases of cell dehydration in sickle cells with the final objective of developing new therapeutic options of patients with sickle cell disease. They represent the logical extension of the productive collaboration and successful studies supported by the present funding cycle.
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Genetic Determinants of Erythrocyte Hydration
  • 批准号:
    7104580
  • 项目类别:
  • 资助金额:
    $59.4万
  • 财政年份:
    2006
  • 负责人:
    Carlo Brugnara
  • 依托单位:
Genetic Determinants of Erythrocyte Hydration
  • 批准号:
    7391161
  • 项目类别:
  • 资助金额:
    $57.76万
  • 财政年份:
    2006
  • 负责人:
    Carlo Brugnara
  • 依托单位:
Genetic Determinants of Erythrocyte Hydration
  • 批准号:
    7590417
  • 项目类别:
  • 资助金额:
    $60.37万
  • 财政年份:
    2006
  • 负责人:
    Carlo Brugnara
  • 依托单位:
Genetic Determinants of Erythrocyte Hydration
  • 批准号:
    7198074
  • 项目类别:
  • 资助金额:
    $57.56万
  • 财政年份:
    2006
  • 负责人:
    Carlo Brugnara
  • 依托单位:
海外基金