Role of calcium channels in the development of diabetic retinopathy

钙通道在糖尿病视网膜病变发展中的作用

基本信息

  • 批准号:
    8635018
  • 负责人:
  • 金额:
    $ 19万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2014
  • 资助国家:
    美国
  • 起止时间:
    2014-02-01 至 2016-01-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): There remains an urgent need to prevent vision loss from diabetic retinopathy (DR), a common and significant problem in patients with diabetes. Preclinical studies have highlighted retinal oxidative stress in the pathogenesis of DR. We reason that identifying the retinal mechanisms mediating pathogenic oxidative stress in diabetes will be important in the development of new and effective treatments. In neurons, oxidative stress and L-type calcium channels (LTCCs) activity are closely linked: increased LTCC activity elevates intracellular calcium content which must then be removed against a steep inter/extracellular calcium concentration gradient via ATP-dependent mechanisms which generate oxygen free radicals. We have discovered that diabetes profoundly changes the overall activity of photoreceptor LTCCs. Remarkably, a non-anti-oxidant and photoreceptor-specific treatment that corrected the abnormal outer retinal LTCC phenotype in vivo concurrently eliminated diabetic retinal oxidative stress. These experiments, using a validated and analytical tool (MEMRI), provide the first evidence for an unexpected and potentially very important discovery linking abnormal photoreceptor LTCCs and oxidative stress in diabetes. In the retina there are 3 major LTCC subtypes (Cav): Cav1.2 (located in inner retina), Cav1.3 (in inner retina, photoreceptor, and retinal pigment epithelium layers), and Cav1.4 (only in photoreceptors. How diabetes alters photoreceptor subtype channels are not yet known. We hypothesized that diabetes induces reproducible abnormalities in photoreceptor Cav1.3 and 1.4 expression and activity, and these changes actively contribute to oxidative stress and diabetic retinopathy. To begin to evaluate our new working hypothesis, we propose the following specific aim, which will take full advantage of our expertise in blending high resolution and analytical in vivo imaging of photoreceptor pathophysiology (manganese-enhanced MRI) with biochemistry (reactive oxygen species, western blot analysis (channel expression)) and histopathology (trypsin digest) in models of DR. SA 1: Test that diabetic alterations in photoreceptor Cav1.3, and 1.4 LTCC activity are required for oxidative stress and DR. The proposed experiments will open up a new line of scientific inquiry that is expected to improve our understanding about the origins of oxidative stress in DR. Because Cav1.3 and 1.4 subtypes are relatively insensitive to commonly used calcium channel blockers, our specific genetic and pharmacological approaches in concert with a novel imaging technique make these studies highly significant. These experiments will be crucial in the identification of new molecular targets for prevention and treatment of DR. The proposed research is highly innovative because it investigates a previously unsuspected but key role of photoreceptor LTCC subtype abnormalities in diabetes-induced oxidative stress, and will thus establish a firm scientific basis for changing current thinking regarding the origins of, and therapeutic options for, pathogenic oxidative stress in DR.
描述(由申请人提供):仍然迫切需要预防糖尿病视网膜病变(DR)导致的视力丧失,这是糖尿病患者常见且严重的问题。临床前研究已经强调了视网膜氧化应激在DR的发病机制中的作用。我们认为,确定糖尿病中介导致病性氧化应激的视网膜机制对于开发新的有效治疗方法将是重要的。 在神经元中,氧化应激和L-型钙通道(LTCC)活性密切相关:LTCC活性增加会升高细胞内钙含量,然后必须通过产生氧自由基的ATP依赖性机制对抗陡峭的细胞间/细胞外钙浓度梯度将其去除。我们已经发现,糖尿病深刻地改变了光感受器LTCC的整体活性。值得注意的是,非抗氧化剂和光感受器特异性治疗,纠正异常的外部视网膜LTCC表型在体内同时消除糖尿病视网膜氧化应激。这些实验使用经过验证的分析工具(MEMRI),为一个意想不到的和潜在的非常重要的发现提供了第一个证据,该发现将异常光感受器LTCC与糖尿病中的氧化应激联系起来。在视网膜中有3种主要的LTCC亚型(Cav):Cav1.2(位于视网膜内层)、Cav1.3(位于视网膜内层、感光细胞和视网膜色素上皮层)和Cav1.4(仅位于感光细胞中)。糖尿病如何改变感光细胞亚型通道尚不清楚。我们假设糖尿病诱导光感受器Cav1.3和1.4表达和活性的可再现异常,这些变化积极促进氧化应激和糖尿病视网膜病变。为了开始评估我们新的工作假设,我们提出了以下具体目标,这将充分利用我们在混合高分辨率和分析感光体病理生理学体内成像方面的专业知识(锰增强MRI)伴生化检查(活性氧,蛋白质印迹分析(通道表达))和组织病理学(胰蛋白酶消化)在DR. SA 1的模型中:检测糖尿病患者光感受器Cav1.3的改变,和1.4 LTCC活性是氧化应激和DR所必需的。拟议的实验将开辟一条新的科学探索路线,由于Cav1.3和1.4亚型对常用的钙通道阻滞剂相对不敏感,我们的特定遗传和药理学方法与新的成像技术相结合,使这些研究非常重要。这些实验对于确定预防和治疗DR的新分子靶点至关重要。拟议的研究具有高度创新性,因为它调查了感光细胞LTCC亚型异常在糖尿病诱导的氧化应激中以前未被怀疑但关键的作用,因此将为改变目前关于糖尿病的起源和治疗选择的想法建立坚实的科学基础。致病性氧化应激

项目成果

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BRUCE A. BERKOWITZ其他文献

BRUCE A. BERKOWITZ的其他文献

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{{ truncateString('BRUCE A. BERKOWITZ', 18)}}的其他基金

Novel Early Retinal Imaging Biomarkers for Treating Later Spatial Memory Loss in Experimental Alzheimer's Disease
用于治疗实验性阿尔茨海默病后期空间记忆丧失的新型早期视网膜成像生物标志物
  • 批准号:
    10650636
  • 财政年份:
    2023
  • 资助金额:
    $ 19万
  • 项目类别:
Mitigating retinitis pigmentosa based on a non-invasive rod energy-landscape biomarker
基于非侵入性棒状能量景观生物标志物减轻色素性视网膜炎
  • 批准号:
    10733154
  • 财政年份:
    2023
  • 资助金额:
    $ 19万
  • 项目类别:
Novel Imaging Biomarker for Treating Spatial Memory Loss in Prodromal Alzheimer's Disease Models
用于治疗前驱阿尔茨海默病模型中空间记忆丧失的新型成像生物标志物
  • 批准号:
    9925773
  • 财政年份:
    2017
  • 资助金额:
    $ 19万
  • 项目类别:
Novel Imaging Biomarker for Treating Spatial Memory Loss in Prodromal Alzheimer's Disease Models
用于治疗前驱阿尔茨海默病模型中空间记忆丧失的新型成像生物标志物
  • 批准号:
    10165441
  • 财政年份:
    2017
  • 资助金额:
    $ 19万
  • 项目类别:
Manganese-enhanced MRI Studies of Retinal Neovascularization
视网膜新生血管的锰增强 MRI 研究
  • 批准号:
    7404426
  • 财政年份:
    2007
  • 资助金额:
    $ 19万
  • 项目类别:
Manganese-enhanced MRI Studies of Retinal Neovascularization
视网膜新生血管的锰增强 MRI 研究
  • 批准号:
    7237746
  • 财政年份:
    2007
  • 资助金额:
    $ 19万
  • 项目类别:
Retinal Oxygenation in Diabetic Retinopathy
糖尿病视网膜病变中的视网膜氧合
  • 批准号:
    6640274
  • 财政年份:
    2002
  • 资助金额:
    $ 19万
  • 项目类别:
Retinal Oxygenation in Diabetic Retinopathy
糖尿病视网膜病变中的视网膜氧合
  • 批准号:
    6544442
  • 财政年份:
    2002
  • 资助金额:
    $ 19万
  • 项目类别:
Retinal Oxygenation in Diabetic Retinopathy
糖尿病视网膜病变中的视网膜氧合
  • 批准号:
    6776347
  • 财政年份:
    2002
  • 资助金额:
    $ 19万
  • 项目类别:
NMR STUDIES OF PRERETINAL NEOVASCULARIZATION
视网膜前新生血管化的核磁共振研究
  • 批准号:
    2163944
  • 财政年份:
    1995
  • 资助金额:
    $ 19万
  • 项目类别:

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