Regulation of vascular leakage in age related macular degeneration

年龄相关性黄斑变性中血管渗漏的调节

基本信息

项目摘要

DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD) is a leading cause of blindness in Americans 60 years of age and older. There are two forms of AMD: Dry or atrophic and Wet or exudative. However, the Wet form of AMD, which is characterized by choroidal neovascularization (CNV), is associated with more severe vision loss caused primarily by the leakage of fluid and blood from the abnormal vessels. Anti-VEGF therapy has emerged as the treatment of choice for patients with wet AMD. However, some patients never respond to anti-VEGF therapy, while still others stop responding after initial success, highlighting the fact that the pathobiology of wet AMD development and progression is still unknown. FasL is an important protein in maintaining immune privilege in the eye, where it is thought to induce apoptosis of infiltrating inflammatory cells. In fact, several reports indicate that FasL expressed on retinal pigment epithelial cells inhibits choroidal neovascularization by triggering apoptosis o vascular endothelial cells. However, FasL exists as both a membrane bound and soluble protein with potentially opposing functions and it is unclear how the different forms of FasL contribute to the development of CNV. We recently developed a unique knock-in mouse strain in which the FasL metalloproteinase cleavage sites were mutated to prevent cleavage of the membrane-bound protein. In these ¿CS mice, FasL is expressed by the physiologically relevant cell types, but these cells are unable to cleave FasL and therefore, can only express mFasL (termed ¿CS mice). For the first time, these mice have allowed us to study the in vivo function of membrane FasL in the absence of soluble FasL. To better understand the function of the different FasL isoforms in the development of choroidal neovascularization, we used a laser-induced murine model of CNV. Our preliminary data indicate that, in ¿CS mice, either the increased expression of mFasL (or the loss of sFasL) prevents vascular leakage following laser induced-CNV. Spectral domain optical coherence tomography (SD-OCT) and Isolectin-B staining demonstrated no difference in the size of the neovascular lesion between ¿CS mice and wild-type mice. However, fluorescein angiography revealed a significant decrease in vascular leakage in ¿CS mice as compared to wild-type mice. These results indicate that membrane FasL does not prevent the ingrowth of choroidal vessels, as previously documented, but rather plays a critical function in preventing vascular leakage, the primary cause of vision loss in patients with wet AMD. We hypothesize that membrane FasL inhibits vascular leakage in laser-induced CNV through Fas mediated pathways triggered in infiltrating macrophages and/or RPE cells. The goals of this proposal are as follows: (Aim 1) Determine whether the decreased vascular leakage in ¿CS mice is due to increased mFasL and/or a lack of sFasL and whether the decreased leakage coincides with a shift in the M1/M2 phenotype of infiltrating macrophages (Aim 2) Establish whether infiltrating macrophages and/or RPE are the critical Fas+ targets through which mFasL mediates inhibition of vascular leakage. PUBLIC HEALTH RELEVANCE: Age Related Macular Degeneration (AMD) is the primary cause of blindness in patients 60 years of age and older. The growth of abnormal blood vessels into the retina is the main cause of severe vision loss, in part due to vessel leakage of blood and fluid that causes damage to the surrounding retinal tissue. We have identified a novel protein that prevents vascular leakage and the goal of this study is to (i) determine whether the administration of this protein can be used to prevent vascular leakage in a mouse model, and (ii) elucidate the mechanism by which this protein functions.
描述(由申请人提供):视网膜相关性黄斑变性(AMD)是导致60岁及以上美国人失明的主要原因。有两种形式的AMD:干性或萎缩性和湿性或渗出性。然而,以脉络膜新生血管形成(CNV)为特征的湿性AMD与主要由流体和血液从异常血管渗漏引起的更严重的视力丧失相关。抗VEGF疗法已成为湿性AMD患者的治疗选择。然而,一些患者从未对抗VEGF治疗作出反应,而另一些患者在初步成功后停止反应,突出了湿性AMD发展和进展的病理生物学仍然未知的事实。FasL是维持眼睛中免疫赦免的重要蛋白质,其中它被认为诱导浸润性炎性细胞的凋亡。事实上,一些报告表明FasL表达了 通过触发血管内皮细胞凋亡抑制脉络膜新生血管形成。然而,FasL作为具有潜在相反功能的膜结合蛋白和可溶性蛋白两者存在,并且不清楚不同形式的FasL如何促进细胞凋亡。 CNV的发展。我们最近开发了一种独特的敲入小鼠品系,其中FasL金属蛋白酶切割位点发生突变,以防止膜结合蛋白的切割。在这些在CS小鼠中,FasL由生理相关的细胞类型表达,但这些细胞不能切割FasL,因此只能表达mFasL(称为CS小鼠)。这是第一次,这些小鼠使我们能够研究在体内功能的膜FasL的可溶性FasL的情况下。为了更好地了解不同的FasL亚型在脉络膜新生血管形成中的作用,我们使用了激光诱导的CNV小鼠模型。我们的初步数据表明,在½ CS小鼠中,mFasL表达的增加(或sFasL的丧失)可以防止激光诱导CNV后的血管渗漏。光谱域光学相干断层扫描(SD-OCT)和Isolectin-B染色显示,CS小鼠和野生型小鼠之间的新生血管病变大小没有差异。然而,荧光素血管造影显示与野生型小鼠相比,CS小鼠的血管渗漏显著减少。这些结果表明,膜FasL不阻止脉络膜血管的向内生长,如先前所记载的,而是在防止血管渗漏中起关键作用,血管渗漏是湿性AMD患者视力丧失的主要原因。我们推测,膜FasL抑制激光诱导的CNV的血管渗漏,通过Fas介导的途径在浸润的巨噬细胞和/或RPE细胞触发。本提案的目标如下:(目的1)确定CS小鼠中血管渗漏减少是否是由于mFasL增加和/或sFasL缺乏所致,以及渗漏减少是否与浸润性巨噬细胞的M1/M2表型转变一致(目的2)确定浸润性巨噬细胞和/或RPE是否是mFasL介导血管渗漏抑制的关键Fas+靶点。 公共卫生相关性:年龄相关性黄斑变性(AMD)是60岁及以上患者失明的主要原因。异常血管生长到视网膜中是严重视力丧失的主要原因,部分原因是血管渗漏血液, 导致周围视网膜组织损伤的液体。我们已经确定了一种新的蛋白质,防止血管渗漏,本研究的目的是(i)确定是否可以使用这种蛋白质的管理,以防止血管渗漏的小鼠模型,和(ii)阐明这种蛋白质的功能机制。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

MEREDITH GREGORY-KSANDER其他文献

MEREDITH GREGORY-KSANDER的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('MEREDITH GREGORY-KSANDER', 18)}}的其他基金

Fas Ligand Cleavage regulates ocular homeostasis and glaucoma
Fas 配体裂解调节眼稳态和青光眼
  • 批准号:
    10374484
  • 财政年份:
    2022
  • 资助金额:
    $ 30.02万
  • 项目类别:
Fas Ligand Cleavage regulates ocular homeostasis and glaucoma
Fas 配体裂解调节眼稳态和青光眼
  • 批准号:
    10867990
  • 财政年份:
    2022
  • 资助金额:
    $ 30.02万
  • 项目类别:
Fas Ligand Cleavage regulates ocular homeostasis and glaucoma
Fas 配体裂解调节眼稳态和青光眼
  • 批准号:
    10550147
  • 财政年份:
    2022
  • 资助金额:
    $ 30.02万
  • 项目类别:
Regulation of the neuroinflammatory response in autoimmune uveitis
自身免疫性葡萄膜炎神经炎症反应的调节
  • 批准号:
    10320063
  • 财政年份:
    2021
  • 资助金额:
    $ 30.02万
  • 项目类别:
Regulation of the neuroinflammatory response in autoimmune uveitis
自身免疫性葡萄膜炎神经炎症反应的调节
  • 批准号:
    10115860
  • 财政年份:
    2021
  • 资助金额:
    $ 30.02万
  • 项目类别:
Regulation of the neuroinflammatory response in autoimmune uveitis
自身免疫性葡萄膜炎神经炎症反应的调节
  • 批准号:
    10527371
  • 财政年份:
    2021
  • 资助金额:
    $ 30.02万
  • 项目类别:
Uncoupling caspase 8-mediated-apotosis from caspase 8-mediated-inflammation in glaucoma.
将青光眼中 caspase 8 介导的细胞凋亡与 caspase 8 介导的炎症解偶联。
  • 批准号:
    9919567
  • 财政年份:
    2019
  • 资助金额:
    $ 30.02万
  • 项目类别:
Regulation of vascular leakage in age related macular degeneration
年龄相关性黄斑变性中血管渗漏的调节
  • 批准号:
    8534134
  • 财政年份:
    2012
  • 资助金额:
    $ 30.02万
  • 项目类别:
Neurotoxicity and neuroprotection in the DBA/2J spontaneous model of glaucoma
DBA/2J 自发性青光眼模型的神经毒性和神经保护
  • 批准号:
    8237645
  • 财政年份:
    2011
  • 资助金额:
    $ 30.02万
  • 项目类别:
Neurotoxicity and neuroprotection in the DBA/2J spontaneous model of glaucoma
DBA/2J 自发性青光眼模型的神经毒性和神经保护
  • 批准号:
    8389866
  • 财政年份:
    2011
  • 资助金额:
    $ 30.02万
  • 项目类别:

相似海外基金

I(eye)-SCREEN: A real-world AI-based infrastructure for screening and prediction of progression in age-related macular degeneration (AMD) providing accessible shared care
I(eye)-SCREEN:基于人工智能的现实基础设施,用于筛查和预测年龄相关性黄斑变性 (AMD) 的进展,提供可及的共享护理
  • 批准号:
    10102692
  • 财政年份:
    2024
  • 资助金额:
    $ 30.02万
  • 项目类别:
    EU-Funded
Inhibiting Neovascularization and Subretinal Fibrosis in Neovascular Age-Related Macular Degeneration
抑制新生血管性年龄相关性黄斑变性的新生血管形成和视网膜下纤维化
  • 批准号:
    10639785
  • 财政年份:
    2023
  • 资助金额:
    $ 30.02万
  • 项目类别:
Inhibition of melanogenesis in retinal pigment epithelium, a contributing factor in age-related macular degeneration
抑制视网膜色素上皮中的黑色素生成,这是年龄相关性黄斑变性的一个促成因素
  • 批准号:
    23K09052
  • 财政年份:
    2023
  • 资助金额:
    $ 30.02万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Deciphering the role of osteopontin in the aging eye and age-related macular degeneration
破译骨桥蛋白在眼睛老化和年龄相关性黄斑变性中的作用
  • 批准号:
    10679287
  • 财政年份:
    2023
  • 资助金额:
    $ 30.02万
  • 项目类别:
Evaluation of New Anti-inflammatory Treatments for Age-Related Macular Degeneration
年龄相关性黄斑变性的新型抗炎治疗方法的评价
  • 批准号:
    10642988
  • 财政年份:
    2023
  • 资助金额:
    $ 30.02万
  • 项目类别:
Progression of Early Atrophic Lesions in Age-related Macular degeneration
年龄相关性黄斑变性早期萎缩性病变的进展
  • 批准号:
    10635325
  • 财政年份:
    2023
  • 资助金额:
    $ 30.02万
  • 项目类别:
Cellular and molecular mechanisms of AIM2 and NLRP3 inflammasome activation in age-related macular degeneration
年龄相关性黄斑变性中 AIM2 和 NLRP3 炎症小体激活的细胞和分子机制
  • 批准号:
    10584110
  • 财政年份:
    2023
  • 资助金额:
    $ 30.02万
  • 项目类别:
Elucidation of roles of mast cells and macrophages in the pathogenesis of age-related macular degeneration
阐明肥大细胞和巨噬细胞在年龄相关性黄斑变性发病机制中的作用
  • 批准号:
    22H03243
  • 财政年份:
    2022
  • 资助金额:
    $ 30.02万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
AMD Mitochondria Modulate Expression of microRNA 135b-5p and 148a-3p in RPE Cybrids: Implications for Age-related Macular Degeneration
AMD 线粒体调节 RPE Cybrids 中 microRNA 135b-5p 和 148a-3p 的表达:对年龄相关性黄斑变性的影响
  • 批准号:
    10433610
  • 财政年份:
    2022
  • 资助金额:
    $ 30.02万
  • 项目类别:
Targeting the inflammatory response in age-related macular degeneration
针对年龄相关性黄斑变性的炎症反应
  • 批准号:
    10504138
  • 财政年份:
    2022
  • 资助金额:
    $ 30.02万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了