CELLULAR DETERMINANTS OF RED CELL SICKLING
CELLULAR DETERMINANTS OF RED CELL SICKLING
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
关键词:
中文摘要
Hb S聚合和镰状化是这一过程的中心事件。
镰状细胞病的病理生理学这些病人的血液
其特征在于存在脱水的致密红细胞,
血红蛋白S浓度升高由于血红蛋白S的增加
浓度显著增加Hb S聚合物的形成速率,
细胞镰状化的程度,一种可能的治疗方法是基于
通过特异性阻断转运防止细胞脱水
参与的途径。两种钾离子外排途径在细胞内钾离子转运中起主要作用。
脱水,即K-C共转运系统和Ca激活的
K频道。K-Cl共转运系统的分子同一性和
钙激活(Gardos)K通道。K-Cl的分子同一性
共转运蛋白(hKCC 1)最近已被阐明。虽然红细胞
Gardo通道尚未克隆,几个相关的Ca门控K通道
大电导(BK)和小电导(SK)的克隆。研究
体外镰状红细胞和体内转基因SAD小鼠,
患有纯合子Hb S(ss)病的患者已经表明,
镰状红细胞可通过特异性阻断Gardos
通过咪唑类抗真菌药克霉唑(CLT)或特异性
通过增加红细胞微克数阻断K-Cl共转运
通过膳食微克补充剂的含量。我们的研究将针对
如下:
1)Gardos通道和K-Cl共转运在镰刀菌脱水中的作用
红细胞和网织红细胞; 2)人红细胞的分子表征
和小鼠红细胞K-Cl协同转运蛋白:这两个研究的主要焦点是
具体目标是分子和生物物理表征的
Gardos通道和K-Cl协同转运蛋白,特别强调这些
可以在小鼠和小鼠中进行治疗操作的性质,
人类,正如我们正在进行的临床和小鼠研究所示。3)效果
K转运途径对红细胞水化状态的体内调节
以及转基因镰状小鼠的镰状病表型:我们将重点关注
关于镰状细胞病在小鼠中的临床表现
模型可以通过调节两者中的任何一个的活性来影响。
运输途径。氯化钾的药理学阻断作用
共运输或Gardos通道将被研究,以及向上的效果-
和K-Cl共转运的下调,
转化到具有高或低K-Cl共转运活性的菌株中,或者通过遗传学方法转化到具有高或低K-Cl共转运活性的菌株中。
操纵K-Cl共转运基因或其调控因子。
这些研究旨在深入了解细胞的基础,
镰状细胞脱水,最终目的是开发新的
镰状细胞病患者的治疗选择。它们代表
生产性合作的逻辑延伸,
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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会议论文
Genetic Determinants of Erythrocyte Hydration
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批准号:7104580
-
项目类别:
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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
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批准号:7391161
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项目类别:
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资助金额:$57.76万
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财政年份:2006
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负责人:Carlo Brugnara
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依托单位:
Genetic Determinants of Erythrocyte Hydration
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批准号:7590417
-
项目类别:
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资助金额:$60.37万
-
财政年份:2006
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负责人:Carlo Brugnara
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依托单位:
Genetic Determinants of Erythrocyte Hydration
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批准号:7198074
-
项目类别:
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资助金额:$57.56万
-
财政年份:2006
-
负责人:Carlo Brugnara
-
依托单位:
EFFECT OF DIETARY MAGNESIUM ON RED CELL MAGNESIUM, VOLUME AND K/CL COTRANSPORT
-
批准号:7204657
-
项目类别:
-
资助金额:$1.02万
-
财政年份:2005
-
负责人:Carlo Brugnara
-
依托单位:
CELLULAR DETERMINANTS OF RED CELL SICKLING
-
批准号:6325889
-
项目类别:
-
资助金额:$26.66万
-
财政年份:2000
-
负责人:Carlo Brugnara
-
依托单位:
EFFECT OF DIETARY MAGNESIUM ON RED CELL MAGNESIUM, VOLUME AND K/CL COTRANSPORT
-
批准号:6120793
-
项目类别:
-
资助金额:$3.04万
-
财政年份:1998
-
负责人:Carlo Brugnara
-
依托单位:
CELLULAR DETERMINANTS OF RED CELL SICKLING
-
批准号:6272518
-
项目类别:
-
资助金额:$27.76万
-
财政年份:1998
-
负责人:Carlo Brugnara
-
依托单位:
LONG TERM USE OF CLOTRIMAZOLE AS A THERAPEUTIC AGENT FOR SICKLE CELL DISEASE
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批准号:6120784
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项目类别:
-
资助金额:$3.04万
-
财政年份:1998
-
负责人:Carlo Brugnara
-
依托单位:
LONG TERM USE OF CLOTRIMAZOLE AS A THERAPEUTIC AGENT FOR SICKLE CELL DISEASE
-
批准号:6220564
-
项目类别:
-
资助金额:$0.07万
-
财政年份:1998
-
负责人:Carlo Brugnara
-
依托单位:
CELLULAR DETERMINANTS OF RED CELL SICKLING
-
批准号:6241523
-
项目类别:
-
资助金额:$47.63万
-
财政年份:1997
-
负责人:Carlo Brugnara
-
依托单位:
EFFECT OF DIETARY MAGNESIUM ON RED CELL MAGNESIUM, VOLUME AND K/CL COTRANSPORT
-
批准号:6251921
-
项目类别:
-
资助金额:$1.92万
-
财政年份:1997
-
负责人:Carlo Brugnara
-
依托单位:
LONG TERM USE OF CLOTRIMAZOLE AS A THERAPEUTIC AGENT FOR SICKLE CELL DISEASE
-
批准号:6281403
-
项目类别:
-
资助金额:$2.01万
-
财政年份:1997
-
负责人:Carlo Brugnara
-
依托单位:
EFFECT OF DIETARY MAGNESIUM ON RED CELL MAGNESIUM, VOLUME AND K/CL COTRANSPORT
-
批准号:6281412
-
项目类别:
-
资助金额:$2.01万
-
财政年份:1997
-
负责人:Carlo Brugnara
-
依托单位:
LONG TERM USE OF CLOTRIMAZOLE AS A THERAPEUTIC AGENT FOR SICKLE CELL DISEASE
-
批准号:6251903
-
项目类别:
-
资助金额:$1.92万
-
财政年份:1997
-
负责人:Carlo Brugnara
-
依托单位:
MAGNESIUM AND SICKLE CELL DISEASE
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批准号:6381018
-
项目类别:
-
资助金额:$22.56万
-
财政年份:1995
-
负责人:Carlo Brugnara
-
依托单位:
MAGNESIUM AND SICKLE CELL DISEASE
-
批准号:2905784
-
项目类别:
-
资助金额:$21.26万
-
财政年份:1995
-
负责人:Carlo Brugnara
-
依托单位:
MAGNESIUM AND SICKLE CELL DISEASE
-
批准号:2151431
-
项目类别:
-
资助金额:$9.9万
-
财政年份:1995
-
负责人:Carlo Brugnara
-
依托单位:
MAGNESIUM AND SICKLE CELL DISEASE
-
批准号:2151432
-
项目类别:
-
资助金额:$13.77万
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财政年份:1995
-
负责人:Carlo Brugnara
-
依托单位:
Magnesium and Sickle Cell Disease
-
批准号:6788763
-
项目类别:
-
资助金额:$20.98万
-
财政年份:1995
-
负责人:Carlo Brugnara
-
依托单位:
海外基金