Role of Caveolin-1 in the Maintenance of Blood-retinal Barrier Integrity

Caveolin-1 在维持血视网膜屏障完整性中的作用

基本信息

项目摘要

Project summary Caveolin-1 (Cav1), traditionally viewed as the signature protein of caveolae membrane domains, plays crucial roles in blood-retinal barrier integrity and retinal inflammation. Gene variants in Cav1 are associated with risk of primary open angle glaucoma and Cav1 protein expression is upregulated in uveitic retinas and in models of diabetic retinopathy. We have found that Cav-1 and caveolae play important roles in blood-retinal barrier (BRB) and inflammation-induced cytokine release. Intriguingly, ablation of Cav1 only from the neuroretinal compartment (Müller glia and neurons) suppresses cytokine release and immune cell influx following inflammatory and neurodegenerative insult. As Cav1 is upregulated in several retinal inflammatory conditions, we hypothesize that local manipulation of Cav1 function presents a viable therapy to suppress retinal inflammatory stress. Given that current steroid-based therapies for retinal inflammatory disease are not completely effective and fraught with potentially severe side effects, we hypothesize that Cav1 represents a novel therapeutic target to suppress retinal inflammation. Thus, it is crucial to understand the function of this protein in the context of the retinal stress adaptation response. We have made the exciting observation that Cav1 in Müller glial cells of the neural retina does not reside within traditional, morphologically-identifiable caveolae. This is because differentiated Müller glia do not normally express significant levels of Cavin1 which, via interaction with Cav1, is necessary to form caveolae. In all tissues studied to date, loss of Cavin1 results in coincident loss of Cav1 protein stability. However, in Müller glia, Cav1 is stably expressed (outside of caveolae) in the absence of Cavin1. This provides a unique opportunity to examine the role of non-caveolar Cav1 in an organ in which Cav1 is associated with human disease. We hypothesize that this non-caveolar localization is crucial to Cav1’s ability to promote secretion of cytokines, chemokines, and growth factors. In this proposal, we will test this novel concept in Müller glia in culture and in vivo by inducing the expression of Cavin1 to sequester Cav1 within caveolae. We will also take advantage of the unusually stable expression of Cav1 outside of caveolae to examine the composition of the non-caveolae Cav1 domain (called herein “Cav1 scaffolds”) and to identify the mechanism by which Cav1 is stably expressed without Cavin1. These goals have clear
项目摘要 Caveolin-1(Cav 1),传统上被认为是Caveolae膜结构域的标志性蛋白, 在血-视网膜屏障完整性和视网膜炎症中起重要作用。Cav 1中的基因变异与 具有原发性开角型青光眼的风险,并且Cav 1蛋白表达在葡萄膜炎视网膜和视网膜中上调 糖尿病视网膜病变的模型。我们发现Cav-1和Caveolae在血视网膜病变中起重要作用, 屏障(BRB)和炎症诱导的细胞因子释放。有趣的是,Cav 1的消融仅来自 神经视网膜隔室(Müller胶质细胞和神经元)抑制细胞因子释放和免疫细胞流入 炎症和神经退行性损伤由于Cav 1在几种视网膜炎症中上调, 我们假设局部操纵Cav 1功能是一种可行的治疗方法, 视网膜炎性应激鉴于目前用于视网膜炎性疾病的基于类固醇的疗法并不 完全有效,并充满了潜在的严重副作用,我们假设Cav 1代表了一种 抑制视网膜炎症的新治疗靶点。因此,理解这一功能至关重要。 蛋白质在视网膜应激适应反应的背景下。我们发现了一个令人兴奋的现象, 神经视网膜Müller神经胶质细胞中的Cav 1不存在于传统的形态学可识别的 小窝这是因为分化的Müller胶质细胞通常不表达显著水平的Cavin 1, 通过与Cav 1相互作用,是形成小窝所必需的。在迄今为止研究的所有组织中,Cavin 1的缺失导致 Cav 1蛋白稳定性的同时丧失。然而,在Müller神经胶质中,Cav 1稳定表达(在细胞外)。 caveolae)在不存在Cavin 1的情况下。这提供了一个独特的机会来研究非小窝的作用, Cav 1在其中Cav 1与人类疾病相关的器官中的表达。我们假设这个非小窝 定位对于Cav 1促进细胞因子、趋化因子和生长因子分泌的能力至关重要。在 我们将在培养的Müller神经胶质细胞和体内通过诱导表达 Cavin 1将Cav 1隔离在小窝内。我们还将利用 Caveolae外的Cav 1以检查非Caveolae Cav 1结构域(本文称为“Cav 1”)的组成 支架”),并鉴定Cav 1在没有Cavin 1的情况下稳定表达的机制。这些目标 明确

项目成果

期刊论文数量(17)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Spatial and temporal localization of caveolin-1 protein in the developing retina.
小窝蛋白-1蛋白在发育中的视网膜中的空间和时间定位。
  • DOI:
    10.1007/978-1-4614-3209-8_3
  • 发表时间:
    2014
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Gu, Xiaowu;Reagan, Alaina;Yen, Allen;Bhatti, Faizah;Cohen, Alex W.;Elliott, Michael H.
  • 通讯作者:
    Elliott, Michael H.
Glucocorticoid-mediated induction of caveolin-1 disrupts cytoskeletal organization, inhibits cell migration and re-epithelialization of non-healing wounds.
  • DOI:
    10.1038/s42003-021-02298-5
  • 发表时间:
    2021-06-18
  • 期刊:
  • 影响因子:
    5.9
  • 作者:
    Jozic I;Abujamra BA;Elliott MH;Wikramanayake TC;Marjanovic J;Stone RC;Head CR;Pastar I;Kirsner RS;Andreopoulos FM;Musi JP;Tomic-Canic M
  • 通讯作者:
    Tomic-Canic M
Caveolin-1 increases proinflammatory chemoattractants and blood-retinal barrier breakdown but decreases leukocyte recruitment in inflammation.
Caveolin-1 会增加促炎化学引诱物和血-视网膜屏障的破坏,但会减少炎症中白细胞的募集。
  • DOI:
    10.1167/iovs.14-14613
  • 发表时间:
    2014
  • 期刊:
  • 影响因子:
    4.4
  • 作者:
    Li,Xiaoman;Gu,Xiaowu;Boyce,TimothyM;Zheng,Min;Reagan,AlainaM;Qi,Hui;Mandal,Nawajes;Cohen,AlexW;Callegan,MichelleC;Carr,DanielJJ;Elliott,MichaelH
  • 通讯作者:
    Elliott,MichaelH
Caveolins and caveolae in ocular physiology and pathophysiology.
  • DOI:
    10.1016/j.preteyeres.2016.09.005
  • 发表时间:
    2017-01
  • 期刊:
  • 影响因子:
    17.8
  • 作者:
    Gu X;Reagan AM;McClellan ME;Elliott MH
  • 通讯作者:
    Elliott MH
Neuroretinal-Derived Caveolin-1 Promotes Endotoxin-Induced Inflammation in the Murine Retina.
  • DOI:
    10.1167/iovs.61.12.19
  • 发表时间:
    2020-10-01
  • 期刊:
  • 影响因子:
    4.4
  • 作者:
    Gurley JM;Gmyrek GB;McClellan ME;Hargis EA;Hauck SM;Dozmorov MG;Wren JD;Carr DJJ;Elliott MH
  • 通讯作者:
    Elliott MH
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MICHAEL H ELLIOTT其他文献

MICHAEL H ELLIOTT的其他文献

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{{ truncateString('MICHAEL H ELLIOTT', 18)}}的其他基金

Caveolae-based mechanosensors for conventional outflow regulation
用于传统流出调节的基于小凹的机械传感器
  • 批准号:
    10186755
  • 财政年份:
    2018
  • 资助金额:
    $ 36.33万
  • 项目类别:
Caveolae-based mechanosensors for conventional outflow regulation
用于传统流出调节的基于小凹的机械传感器
  • 批准号:
    9596193
  • 财政年份:
    2018
  • 资助金额:
    $ 36.33万
  • 项目类别:
P30 Center Core Grant for Vision Research
P30 中心视觉研究核心资助
  • 批准号:
    10272006
  • 财政年份:
    2011
  • 资助金额:
    $ 36.33万
  • 项目类别:
P30 Center Core Grant for Vision Research
P30 中心视觉研究核心资助
  • 批准号:
    10696214
  • 财政年份:
    2011
  • 资助金额:
    $ 36.33万
  • 项目类别:
P30 Center Core Grant for Vision Research
P30 中心视觉研究核心资助
  • 批准号:
    10477424
  • 财政年份:
    2011
  • 资助金额:
    $ 36.33万
  • 项目类别:
Role of Caveolin-1 in the Maintenance of Blood-retinal Barrier Integrity
Caveolin-1 在维持血视网膜屏障完整性中的作用
  • 批准号:
    8963726
  • 财政年份:
    2009
  • 资助金额:
    $ 36.33万
  • 项目类别:
Role of caveolin-1 in the maintenance of blood-retinal barrier integrity
Caveolin-1 在维持血视网膜屏障完整性中的作用
  • 批准号:
    9563983
  • 财政年份:
    2009
  • 资助金额:
    $ 36.33万
  • 项目类别:
Role of Caveolin-1 in the Maintenance of Blood-retinal Barrier Integrity
Caveolin-1 在维持血视网膜屏障完整性中的作用
  • 批准号:
    10475582
  • 财政年份:
    2009
  • 资助金额:
    $ 36.33万
  • 项目类别:
Role of Caveolin-1 in the Maintenance of Blood-retinal Barrier Integrity
Caveolin-1 在维持血视网膜屏障完整性中的作用
  • 批准号:
    8197255
  • 财政年份:
    2009
  • 资助金额:
    $ 36.33万
  • 项目类别:
Role of Caveolin-1 in the Maintenance of Blood-retinal Barrier Integrity
Caveolin-1 在维持血视网膜屏障完整性中的作用
  • 批准号:
    7783730
  • 财政年份:
    2009
  • 资助金额:
    $ 36.33万
  • 项目类别:

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cGAS-STING 通路靶向具有 CD46 趋向性和 AFP 启动子的复制腺病毒条件性复制限制用于治疗肝细胞癌
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针对间皮瘤中发现的特征基因突变的具有复制能力的腺病毒的分子疗法
  • 批准号:
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溶瘤腺病毒和免疫代谢佐剂治疗胶质瘤
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    10330464
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禽腺病毒的分子生物学和发病机制
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    41625-2013
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