REGULATION OF RENAL BICARBONATE AND CHLORIDE ABSORPTION
肾脏碳酸氢盐和氯化物吸收的调节
基本信息
- 批准号:2900208
- 负责人:
- 金额:$ 29.69万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1987
- 资助国家:美国
- 起止时间:1987-07-01 至 2001-03-31
- 项目状态:已结题
- 来源:
- 关键词:acidity /alkalinity angiotensin II antiport binding proteins endothelin gene expression genetic transcription genetically modified animals hormone regulation /control mechanism laboratory mouse laboratory rat membrane transport proteins posttranslational modifications protein biosynthesis protein isoforms protein transport protein tyrosine kinase protooncogene renal tubular transport renal tubule acidosis tissue /cell culture
项目摘要
Significant evidence exists suggesting that NHE-3, an Na/H antiporter
isoform, encodes a significant fraction of proximal tubule apical membrane
Na/H antiporter activity. The overall aim of the present studies is to
examine the molecular mechanisms responsible for regulation of NHE-3. In
Aim l, studies will examine chronic regulation of NHE-3 in three settings,
chronic acidosis, chronic increases in tonicity, and chronic increases in
cell cAMP levels. The majority of the studies will be performed in
cultured cells, and will examine whether effects on NHE-3 activity in
these models are mediated by: 1) changes in mRNA abundance due to either
changes in transcription rate or mRNA stability, 2) changes in protein
abundance due to changes in synthesis rate or stability, 3) cellular
trafficking, 4) posttranslational modification of NHE-3; or 5) regulation
of a binding protein. Where appropriate, studies will he performed in vivo
in rats to determine whether findings in cell culture apply.
In preliminary studies, we have demonstrated that chronic acidosis
activates c-src, and inhibition of src family nonreceptor tyrosine kinases
prevents acid-induced activation of NHE-3. In Aim 2, studies will address
the molecular mechanisms by which c-src is activated, and the role of c-
src in the regulation of renal acidification. Specifically, studies will
examine whether the effect of pH on c-src is specific for proximal tubule
cells or occurs in other cells, and whether the effect is specific for c-
src or also involves other src family nonreceptor tyrosine kinases.
Studies will then examine how c-src is modified by acid with respect to
phosphorylation, binding, and localization within cells. Studies will
address whether overexpression of a constitutively activated c-src
increases Na/H antiporter activity. Using mice in which the c-src gene or
the c-yes gene has been disrupted, we will examine the role of these
kinases in the regulation of renal acidification in vivo. Lastly, studies
will address whether c-src plays a role in acid-induced immediate early
gene activation and in hormonal activation of the Na/H antiporter.
The last aim will address the molecular mechanisms by which angiotensin II
and endothelin regulate NHE-3 activity. Mechanisms addressed will focus on
trafficking and posttranslational modification. Studies will also measure
ambient endothelin levels in the proximal tubule. Lastly, mice in which
the genes for ET-3 or ETB have been disrupted, will be used to study the
role of this pathway in the regulation of renal function.
有重要证据表明,NHE-3,一种Na/H反向转运蛋白,
同种型,编码近端小管顶膜的重要部分
Na/H逆向转运蛋白活性。本研究的总体目标是
研究负责调节NHE-3的分子机制。在
目的1,研究将在三种情况下检查NHE-3的慢性调节,
慢性酸中毒,张力慢性增加,
细胞cAMP水平。大多数研究将在
培养的细胞,并将检查是否对NHE-3活性的影响,
这些模型由以下因素介导:1)mRNA丰度的变化,
转录速率或mRNA稳定性的变化,2)蛋白质
由于合成速率或稳定性的变化而导致的丰度,3)细胞
运输,4)NHE-3的翻译后修饰;或5)调节
一种结合蛋白。适当时,将在体内进行研究
以确定细胞培养中的发现是否适用。
在初步研究中,我们已经证明慢性酸中毒
激活c-src,并抑制src家族非受体酪氨酸激酶
防止酸诱导的NHE-3活化。在目标2中,研究将解决
c-src被激活的分子机制,以及c-src的作用。
SRC在调节肾脏酸化中的作用。具体而言,研究将
检查pH对c-src的影响是否对近端小管特异
细胞或发生在其他细胞中,以及该效应是否特异于c-
src或还涉及其它src家族非受体酪氨酸激酶。
然后研究c-src如何被酸修饰,
细胞内的磷酸化、结合和定位。研究将
解决组成性激活的c-src的过表达是否
增加Na/H逆向转运蛋白活性。使用小鼠,其中c-src基因或
c-yes基因已经被破坏,我们将研究这些基因的作用。
激酶在体内肾脏酸化调节中的作用。最后,研究
将讨论c-src是否在酸诱导的即刻早期
基因激活和Na/H反向转运蛋白的激素激活。
最后一个目标是解决血管紧张素II的分子机制,
内皮素调节NHE-3活性。所涉及的机制将侧重于
运输和翻译后修饰。研究还将衡量
近端小管中的环境内皮素水平。最后,小鼠,
ET-3或ETB的基因已被破坏,将用于研究
该途径在调节肾功能中的作用。
项目成果
期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
专利数量(0)
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