RBC Ion Transporters as Hemoglobinopathy Risk Modifiers

红细胞离子转运蛋白作为血红蛋白病风险调节剂

基本信息

批准号：
7629010
负责人：
SETH Leo ALPER
金额：
$ 39.02万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-06-15 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7629010
关键词：
Blood Blood capillaries Bone Marrow Transplantation Calcium-Activated Potassium Channel Cations Cell Volumes Cell membrane Cervix Neoplasms Clinical Clinical Trials Cooley&apos s anemia Dehydration Development Doctor of Philosophy Dominant-Negative Mutation Epithelial Erythrocytes Erythroid Event Finding of Mean Corpuscular Hemoglobin Genes Genetic Genetic screening method Growth Hemoglobin Hemoglobinopathies Human In Vitro Ion Transport Ions Lead Mammary gland Mediating Mediator of activation protein Membrane Modeling Molecular Weight Mus Neoplasm Transplantation Nude Mice Orphan Drugs Ovary Pathologic Pathway interactions Patients Permeability Pharmaceutical Preparations Pharmacotherapy Phase Phenotype Physiological Potassium Channel Publishing Recombinants Regulation Research Personnel Risk Secondary to Severities Severity of illness Sickle Cell Sickle Cell Anemia Sickle Hemoglobin Sum Supplementation Syndrome System Testing Thalassemia Thalassemia intermedia Time Translational Research Up-Regulation Variant Vascular Diseases Work base beta Thalassemia capillary design disorder prevention drug development gene replacement hydroxyurea in vivo inhibitor/antagonist mouse model novel palliative polymerization polypeptide prevent programs prototype research clinical testing research study routine therapy sickling standard care therapeutic target

项目摘要

Description (provided by applicant): Sickle cell disease and thalassemia are characterized by pathological red cell dehydration. The mean corpuscular hemoglobin concentration of sickle erythrocytes critically determines the lag time preceding the rapid phase of deoxygenation-induced polymerization of hemoglobin S. Several erythroid ion transporters and channels are believed on the basis of pharmacological and physiological studies to regulate red cell hemoglobin concentration secondary to regulation of red cell volume. Among these activities already studied as therapeutic targets in sickle cell disease are the KCNN/IK1/SK4 Ca2+-activated K+ channel of intermediate conductance (Gardos channel), several types of KCC K-CI cotransporters, at least two types of erythroid CI- conductance, and at least one type of Ca2+permeable cation conductance. The K-CI cotransporters have also been tested as therapeutic targets for thalassemia. The genes encoding these ion-transporting polypeptides are strong candidate risk modifier genes for the hemoglobinopathies. This application proposes the general hypothesis that genetic modulation of these transporter and channel activities will modulate disease severity in mouse models of hemoglobinopathies. This general hypothesis will be tested by experiments designed to pursue the following Specific Aims: Aim 1. We will test the hypothesis that genetic deficiency of the erythroid IK1/Gardos channel will decrease pathologic red cell dehydration and will ameliorate clinical severity in mouse models of sickle cell disease. Aim 2. We will test the hypothesis that genetic deficiency of erythroid KCC K-CI cotransporters will decrease pathologic red cell dehydration and will ameliorate clinical severity in mouse models of sickle cell disease and of beta-thalassemia intermedia. Aim 3. We will test the hypothesis that combined genetic deficiency of erythroid IK1/Gardos channel and of erythroid KCC K-CI cotransporters will further ameliorate clinical severity in mouse models of sickle cell disease. The proposed experiments will increase understanding of sickle cell disease and thalassemia by providing mouse models for genetic tests of new drug therapies under development for near-term clinical testing.

描述（由申请人提供）：镰状细胞疾病和地中海贫血的特征是病理红细胞脱水。镰状红细胞的平均肺泡血红蛋白浓度批判性地确定了在氧化诱导的血红蛋白S的快速相位之前的滞后时间。几个红细胞离子转运蛋白和通道基于药理和物理学研究的基础，以调节红细胞浓度的构造，以调节红细胞浓缩量为重量的conformation condrimation Redeariation in Swine condection Redeariation in Swine condection Redy Collation in Shectry in Shectry seconfors in Swine condection in Swine in Swine condection Red Cellighy swindy condrys。在镰状细胞疾病中已经研究的这些活动中，有KCNN/IK1/SK4 CA2+激活的K+中间电导的K+通道（Gardos Channel），几种类型的KCC K-CI共转运蛋白，至少两种类型的Erythroid Ci-Gustance，至少一种类型的Ca2 Ca2+允许的染色+允许的染色。 K-CI共转运蛋白也已被测试为thalassyalassya的治疗靶标。编码这些离子传输多肽的基因是血红蛋白病的强烈候选风险修饰基因。该应用提出了一般假设，即这些转运蛋白的遗传调节和通道活性将在血红蛋白病小鼠模型中调节疾病的严重程度。该总体假设将通过旨在追求以下特定目的的实验进行检验：目标1。我们将检验以下假设：红细胞IK1/Gardos通道的遗传缺乏将减少病理红细胞脱水，并将在小鼠细胞疾病的小鼠模型中减轻临床严重性。 AIM 2。我们将检验以下假设：红细胞KCC KCC CI共转运蛋白的遗传缺乏将降低病理红细胞脱水，并在镰状细胞疾病和β-丘脑中二硫代症中的小鼠模型中改善临床严重程度。 AIM 3。我们将检验以下假设：红细胞IK1/GARDOS通道和红细胞KCC KCC KCI共转运蛋白的遗传缺陷将进一步改善小鼠细胞疾病模型中的临床严重程度。提出的实验将通过为正在开发的新药物疗法的基因测试提供小鼠模型来增加对镰状细胞疾病和丘脑性的了解，以进行近期临床测试。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Genetic disruption of KCC cotransporters in a mouse model of thalassemia intermedia.

中间型地中海贫血小鼠模型中 KCC 协同转运蛋白的基因破坏。

DOI：
10.1016/j.bcmd.2019.102389
发表时间：
2020
期刊：
Blood cells, molecules & diseases
影响因子：
0
作者：
Shmukler,BorisE;Rivera,Alicia;Bhargava,Parul;Nishimura,Katherine;Kim,EdwardH;Hsu,Ann;Wohlgemuth,JayG;Morton,James;Snyder,LMichael;DeFranceschi,Lucia;Rust,MarcoB;Hubner,ChristianA;Brugnara,Carlo;Alper,SethL
通讯作者：
Alper,SethL

Erythroid-specific inactivation of Slc12a6/Kcc3 by EpoR promoter-driven Cre expression reduces K-Cl cotransport activity in mouse erythrocytes.

DOI：
10.14814/phy2.15186
发表时间：
2022-03
期刊：
Physiological reports
影响因子：
2.5
作者：
Shmukler BE;Rivera A;Nishimura K;Hsu A;Wohlgemuth JG;Dlott JS;Michael Snyder L;Brugnara C;Alper SL
通讯作者：
Alper SL

Combined genetic disruption of K-Cl cotransporters and Gardos channel KCNN4 rescues erythrocyte dehydration in the SAD mouse model of sickle cell disease.

K-Cl 协同转运蛋白和 Gardos 通道 KCNN4 的联合基因破坏可挽救镰状细胞病 SAD 小鼠模型中的红细胞脱水。

DOI：
10.1016/j.bcmd.2019.102346
发表时间：
2019
期刊：
Blood cells, molecules & diseases
影响因子：
0
作者：
Shmukler,BorisE;Rivera,Alicia;Bhargava,Parul;Nishimura,Katherine;Hsu,Ann;Kim,EdwardH;Trudel,Marie;Rust,MarcoB;Hubner,ChristianA;Brugnara,Carlo;Alper,SethL
通讯作者：
Alper,SethL

N-ethylmaleimide activates a Cl(-)-independent component of K(+) flux in mouse erythrocytes.

N-乙基马来酰亚胺可激活小鼠红细胞中 K() 通量的独立于 Cl(-) 的成分。

DOI：
10.1016/j.bcmd.2013.02.004
发表时间：
2013
期刊：
Blood cells, molecules & diseases
影响因子：
0
作者：
Shmukler,BorisE;Hsu,Ann;Alves,Jessica;Trudel,Marie;Rust,MarcoB;Hubner,ChristianA;Rivera,Alicia;Alper,SethL
通讯作者：
Alper,SethL