Na+/H+-exchanger-1 and Diabetic Neuropathy

Na /H -exchanger-1 和糖尿病神经病变

基本信息

项目摘要

DESCRIPTION (provided by applicant): Evidence for importance of oxidative-nitrosamine stress in peripheral diabetic neuropathy (PDN) is emerging, but the mechanisms are not well understood. Up regulation of Na? exchanger-1 (NHE-1), previously demonstrated in several tissue-sites for diabetes complications, causes an increase in cytosolic ph and related activation of the upper part of glycolysis. The overall hypothesis of this proposal is that NHE-1 plays an important role in PDN, because NHE-1-driven activation of the upper part of glycolysis, under conditions of diabetes-induced inhibition (endothelial cells) or insufficient activation (Schwann cells, SC) of glyceraldehyde- 3-phosphate dehydrogenate, underlies diversion of the excessive glycolytic flux towards formation of a-glycerophosphate and methylglyoxal, with resulting activation of two major free radical-generating mechanisms i.e., non-enzymatic glycation and NAD(P)H oxidase. In support of this hypothesis, our preliminary studies have shown that 1) NHE-1 is abundantly expressed in rat and mouse peripheral nerve, rat DRG neurons, and human SC; 2) HSC basal ph and NHE-1 expression and activity increase in response to high glucose; 3) the upper part of glycolysis is activated in the diabetic peripheral nerve; 4) the specific NHE-1 inhibitor cariporide, at least, partially prevents nerve conduction deficits, sensory neuropathy, neurovascular dysfunction, and metabolic imbalances in STZ-diabetic rats; 5) STZ-diabetic NHE-1 mice develop less severe PDN than STZ-diabetic wild-type mice. The OBJECTIVE of this proposal is to evaluate the role of NHE-1 in PDN in animal models of Type 1 and Type 2 diabetes. The specific aims are 1) elucidate if NHE-1 inhibition reverses PDN in STZ- diabetic and ZDF rats; 2) determine the roles of HIF-1a and aldosterone in diabetes- and high glucose-induced NHE-1 overexpression; and 3) evaluate the contribution of NHE-1 to oxidative-nitrosative stress in peripheral nerve, vasa nervorum, spinal cord, and DRG neurons of diabetic rats and high glucose-exposed cultured HSC and co-cultured rat SC and DRG neurons. The project combines physiological, behavioral, biochemical, immunohistochemical, and structural studies in animal models with molecular studies in cultured HSC and co- cultured rat SC and DRG neurons. The findings will generate new information on the role for NHE-1 in PDN in two types of diabetes and may provide rationale for development of NHE-1 inhibitors and NHE-1 inhibitor- containing drug combinations. PUBLIC HEALTH RELEVANCE: Peripheral diabetic neuropathy (PDN) is the most devastating complication of diabetes mellitus, and a leading cause of foot amputation. Evidence for importance of free radicals and oxidants in PDN is emerging from both animal and human studies, but the mechanisms are not well understood. Upregulation of Na? exchanger-1 (NHE-1), previously demonstrated in several tissues of diabetic animals, causes an increase in cytosolic ph and related activation of the upper part of glycolysis. The overall hypothesis of this proposal is that NHE-1 plays an important role in PDN, because NHE-1-driven activation of the upper part of glycolysis, under conditions of diabetes-induced inhibition (endothelial cells) or insufficient activation (Schwann cells, SC) of glyceraldehyde-3-phosphate dehydrogenase, underlies diversion of the excessive glycolytic flux towards two major free radical-generating pathways i.e., non-enzymatic glycation and NAD (P) H oxidase. The hypothesis is supported by our preliminary data demonstrating that 1) NHE-1 is abundantly expressed in rat and mouse peripheral nerve, rat DRG neurons, and human SC; 2) HSC basal ph and NHE-1 expression and activity are increased by high glucose; 3) the upper part of glycolysis is activated in the diabetic nerve; 4) the specific NHE- 1 inhibitor cariporide, at least, partially prevents PDN in STZ-diabetic rats; 5) diabetic NHE-1 mice develop less severe PDN than diabetic mice with normal NHE-1 content. The OBJECTIVE of this proposal is to evaluate the role of NHE-1 in PDN in animal models of Type 1 and Type 2 diabetes. The SPECIFIC AIMS are 1) elucidate if NHE-1 inhibition reverses PDN in STZ-diabetic and ZDF rats; 2) evaluate the mechanisms of diabetes-induced NHE-1 over expression; and 3) assess the contribution of NHE-1 to oxidative-nitrosative stress in peripheral nervous system of diabetic rats and high glucose-exposed cultured HSC and co-cultured rat SC and DRG neurons. The project combines physiological, behavioral, biochemical, immunohistochemical, and structural studies in animal's models with molecular studies in cell cultures. The findings will generate new information on the role for NHE-1 in PDN in two types of diabetes and may provide rationale for development of NHE-1 inhibitors and NHE-1 inhibitor-containing drug combinations for prevention and treatment of PDN.
描述(由申请人提供):氧化亚硝胺应激在糖尿病周围神经病变(PDN)中的重要性的证据正在出现,但其机制尚不清楚。上调Na?先前在糖尿病并发症的几个组织部位中证实的交换器-1(NHE-1)引起细胞溶质pH的增加和糖酵解上部的相关活化。该建议的总体假设是,NHE-1在PDN中起重要作用,因为在糖尿病诱导的抑制条件下,NHE-1驱动糖酵解的上部的激活(内皮细胞)或活化不足(Schwann细胞,SC)的糖酵解,是过度糖酵解通量转向形成α-甘油磷酸和甲基乙二醛的基础,导致两种主要的自由基产生机制的活化即,非酶糖化和NAD(P)H氧化酶。为支持这一假说,我们的初步研究表明:1)NHE-1在大鼠和小鼠外周神经、大鼠DRG神经元和人SC中大量表达; 2)HSC基础ph和NHE-1表达和活性响应于高糖而增加; 3)糖酵解的上部在糖尿病外周神经中被激活; 4)特异性NHE-1抑制剂cariporide至少部分地预防STZ糖尿病大鼠中的神经传导缺陷、感觉神经病变、神经血管功能障碍和代谢失衡; 5)STZ糖尿病NHE-1小鼠比STZ糖尿病野生型小鼠发展较不严重的PDN。本研究的目的是在1型和2型糖尿病动物模型中评价NHE-1在PDN中的作用。具体目的是1)阐明NHE-1抑制是否逆转STZ-糖尿病和ZDF大鼠中的PDN; 2)确定HIF-1 α和醛固酮在糖尿病和高糖诱导的NHE-1过表达中的作用; 3)研究NHE-1在外周神经、神经血管、脊髓、观察糖尿病大鼠、高糖暴露培养的HSC及SC与DRG神经元共培养的大鼠DRG神经元的变化。该项目结合了生理学、行为学、生物化学、免疫组织化学和动物模型的结构研究,以及培养的HSC和共培养的大鼠SC和DRG神经元的分子研究。这些发现将产生关于NHE-1在两种类型糖尿病的PDN中的作用的新信息,并可能为开发NHE-1抑制剂和含NHE-1抑制剂的药物组合提供理论基础。公共卫生相关性:糖尿病周围神经病变(PDN)是糖尿病最严重的并发症,也是导致足部截肢的主要原因。自由基和氧化剂在PDN中的重要性的证据来自动物和人类研究,但其机制尚不清楚。上调钠?先前在糖尿病动物的几种组织中证实的交换器-1(NHE-1)引起细胞溶质pH的增加和糖酵解上部的相关活化。该提议的总体假设是NHE-1在PDN中起重要作用,因为在糖尿病诱导的甘油醛-3-磷酸脱氢酶的抑制(内皮细胞)或不充分活化(许旺细胞,SC)的条件下,NHE-1驱动的糖酵解上部的活化是过度糖酵解通量转向两个主要自由基产生途径的基础,即,非酶糖化和NAD(P)H氧化酶。我们的初步数据支持了这一假设,表明1)NHE-1在大鼠和小鼠外周神经、大鼠DRG神经元和人SC中大量表达; 2)HSC基础pH和NHE-1表达和活性被高糖增加; 3)糖酵解的上部在糖尿病神经中被激活; 4)特异性NHE- 1抑制剂cariporide至少部分地预防STZ糖尿病大鼠中的PDN; 5)糖尿病NHE-1小鼠比具有正常NHE-1含量的糖尿病小鼠发展较不严重的PDN。本研究的目的是在1型和2型糖尿病动物模型中评价NHE-1在PDN中的作用。具体目的是1)阐明NHE-1抑制是否逆转STZ糖尿病和ZDF大鼠中的PDN; 2)评估糖尿病诱导的NHE-1过表达的机制;和3)评估NHE-1对糖尿病大鼠外周神经系统和高糖暴露培养的HSC以及共培养的大鼠SC和DRG神经元中氧化-亚硝化应激的贡献。该项目将动物模型中的生理学、行为学、生物化学、免疫组织化学和结构研究与细胞培养中的分子研究相结合。这些发现将产生关于NHE-1在两种类型糖尿病PDN中的作用的新信息,并可能为开发NHE-1抑制剂和含NHE-1底物的药物组合用于预防和治疗PDN提供理论基础。

项目成果

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IRINA G OBROSOVA其他文献

IRINA G OBROSOVA的其他文献

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{{ truncateString('IRINA G OBROSOVA', 18)}}的其他基金

Peroxynitrite, protein nitration and advanced diabetic neuropathy
过氧亚硝酸盐、蛋白质硝化和晚期糖尿病神经病变
  • 批准号:
    8053412
  • 财政年份:
    2010
  • 资助金额:
    $ 31.41万
  • 项目类别:
Peroxynitrite, protein nitration and advanced diabetic neuropathy
过氧亚硝酸盐、蛋白质硝化和晚期糖尿病神经病变
  • 批准号:
    8243618
  • 财政年份:
    2010
  • 资助金额:
    $ 31.41万
  • 项目类别:
Peroxynitrite, protein nitration and advanced diabetic neuropathy
过氧亚硝酸盐、蛋白质硝化和晚期糖尿病神经病变
  • 批准号:
    7792652
  • 财政年份:
    2010
  • 资助金额:
    $ 31.41万
  • 项目类别:
Na+/H+-exchanger-1 and Diabetic Neuropathy
Na /H -exchanger-1 和糖尿病神经病变
  • 批准号:
    7640601
  • 财政年份:
    2008
  • 资助金额:
    $ 31.41万
  • 项目类别:
Na+/H+-exchanger-1 and Diabetic Neuropathy
Na /H -exchanger-1 和糖尿病神经病变
  • 批准号:
    8279360
  • 财政年份:
    2008
  • 资助金额:
    $ 31.41万
  • 项目类别:
12/15-Lipoxygenase and Diabetic Neuropathy
12/15-脂氧合酶和糖尿病神经病变
  • 批准号:
    7314920
  • 财政年份:
    2007
  • 资助金额:
    $ 31.41万
  • 项目类别:
12/15-Lipoxygenase and Diabetic Neuropathy
12/15-脂氧合酶和糖尿病神经病变
  • 批准号:
    7640931
  • 财政年份:
    2007
  • 资助金额:
    $ 31.41万
  • 项目类别:
12/15-Lipoxygenase and Diabetic Neuropathy
12/15-脂氧合酶和糖尿病神经病变
  • 批准号:
    8085917
  • 财政年份:
    2007
  • 资助金额:
    $ 31.41万
  • 项目类别:
12/15-Lipoxygenase and Diabetic Neuropathy
12/15-脂氧合酶和糖尿病神经病变
  • 批准号:
    7777475
  • 财政年份:
    2007
  • 资助金额:
    $ 31.41万
  • 项目类别:
12/15-Lipoxygenase and Diabetic Neuropathy
12/15-脂氧合酶和糖尿病神经病变
  • 批准号:
    7467273
  • 财政年份:
    2007
  • 资助金额:
    $ 31.41万
  • 项目类别:

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