Fas Ligand Cleavage regulates ocular homeostasis and glaucoma
Fas 配体裂解调节眼稳态和青光眼
基本信息
- 批准号:10374484
- 负责人:
- 金额:$ 61.96万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-02-01 至 2026-01-31
- 项目状态:未结题
- 来源:
- 关键词:AddressApoptosisApoptoticAstrocytesBindingBlindnessCD95 AntigensCause of DeathCell DeathCellsCessation of lifeChimera organismChronic DiseaseDangerousnessDataDefectDevelopmentDiseaseEffector CellEmbryoEnvironmentEquilibriumExtracellular DomainEyeEye diseasesFamilyFluorochromeGene ExpressionGene TargetingGenetic TranscriptionGlaucomaGlial Fibrillary Acidic ProteinGoalsGrantHomeostasisImmuneInflammationInjectionsIntegral Membrane ProteinLengthLigandsLinkMediatingMediator of activation proteinMembraneMetalloproteasesMicrospheresModelingMonitorMorulaMuller&aposs cellMusMutateMutationNeurogliaOcular PathologyOnset of illnessOptic DiskOptic NerveOutcomePathogenesisPathologicPathologyPathway interactionsPatientsPeptide HydrolasesPreventionProcessProductionProtein FragmentProtein IsoformsRegulationResearchRetinaRetinal Ganglion CellsRoleSignal PathwaySignal TransductionSiteSourceTIMP1 geneTNF geneTamoxifenTherapeuticTimeTissue Inhibitor of Metalloproteinase-1TissuesTransfectionTumor Necrosis Factor Ligand Superfamily Member 6Vascular Endothelial Cellcell typechemokinecytokineimprovedinsightintravitreal injectionmacrogliamembrane activityneurotoxicnew therapeutic targetnoveloverexpressionpreventprogramsreceptorrecruitsortasesystemic autoimmune diseasetherapeutic targettoolvector
项目摘要
The type II transmembrane protein Fas ligand (Fasl) was first identified as a death receptor ligand that induced
Fas+ target cells to undergo apoptosis. As such, its constitutive expression in the eye has historically been linked
to the phenomenon of immune privilege and its ability to kill activated eye-infiltrating Fas+ effector cells, or eye-infiltrating
Fas+ vascular endothelial cells. However, this notion is confounded by the fact that many non-hematopoietic
cell types in the eye, including retinal ganglion cells (RGCs), constitutively express Fas. In fact,
Fasl-mediated destruction of RGCs is a key factor in glaucoma pathogenesis, either by direct killing of RGCs
and/or by inducing the production of proinflammatory chemokines by Fas+ glial cells (eg. astrocytes), that recruit
proinflammatory cells to the retina and thereby causing neurotoxic inflammation. This apparent conundrum can
be explained if one accepts our hypothesis that constitutive metalloproteinase-mediated cleavage of
membraned-bound Fasl (mFasL), releases a soluble fragment (sFasL) that opposes the neurotoxic activity of
mFasL. This premise is supported by preliminary data showing: (a) mice with a gene-targeted mutation of Fasl
that eliminates this Fasl cleavage site (mFaslmice) develop accelerated glaucoma in spontaneous and
inducible glaucoma models; {b} in healthy eyes, retinal Fasl is constitutively cleaved, but in glaucomatous eyes,
retinal Fasl is membrane-bound; and (c) intravitreal injection of an AAV2-sFasL vector prior to disease onset
can prevent the development of glaucoma, while injection of AAV2-sFasL after disease onset can reverse
functional defects. Together, these data point to Fasl as an important therapeutic target for patients with
glaucoma. However, a number of key questions remain unanswered and will be addressed by the proposed 3
specific aims: (Aim 1) When and how is Fasl cleavage suppressed during the development and progression of
glaucoma and how do ADAM10 and TIMP1 in regulate Fasl cleavage ?; (Aim 2) To what extent does the direct
engagement of Fas, expressed by astrocytes and/or RGCs, contribute to the development of glaucoma?; and
(Aim 3) Can sFasL directly engage Fas to elicit a protective gene expression program? Our research strategy
will involve both accepted and novel experimental tools, including (a) sortase-tagged-Fasl mice (provide by Dr.
Ploegh}, that will greatly facilitate our ability to monitor mFasL vs sFasL protein levels in the eye, {b} Fas-flexed
mice crossed to RGC- and astrocyte/muller-specific ere-deleter lines, that will allow us to identify the importance
of these cells in the development of glaucoma; (c) allophenic (tetraparental) chimeric mice made by fusing Fas+
and Fasn•9 embryos, that will allow us to distinguish direct and indirect effects of Fasl engagement in the context
of glaucoma, and {d} AAV2-sFasL vectors that will allow us to determine if sFasL functions independently of
mFasL. The mechanistic insights gained from the proposed studies are likely to reveal improved strategies for
the effective manipulation of Fas/Fasl interactions in patients afflicted with glaucoma and other ocular disorders.
II型跨膜蛋白Fas配体(Fas 1)首先被鉴定为死亡受体配体,
Fas+靶细胞进行凋亡。因此,其在眼睛中的组成性表达在历史上与
免疫赦免现象及其杀死活化的眼浸润Fas+效应细胞或眼浸润Fas+效应细胞的能力,
Fas+血管内皮细胞。然而,这一概念是混淆的事实,许多非造血
眼睛中的细胞类型,包括视网膜神经节细胞(RGC),组成型表达Fas。事实上,
FasL介导的RGCs的破坏是青光眼发病机制中的关键因素,无论是通过直接杀死RGCs
和/或通过诱导Fas+神经胶质细胞产生促炎趋化因子(例如,星形胶质细胞),
促炎细胞进入视网膜,从而引起神经毒性炎症。这个明显的难题可以
如果接受我们的假设,即组成型金属蛋白酶介导的切割,
膜结合的FasL(mFasL),释放可溶性片段(sFasL),其对抗
mFasL。这一前提得到了初步数据的支持,这些数据显示:(a)具有FasL基因靶向突变的小鼠,
在自发性青光眼中,
诱导型青光眼模型; {B}在健康的眼睛中,视网膜FasL是组成性裂解的,但是在青光眼眼睛中,
视网膜FasL是膜结合的;和(c)在疾病发作之前玻璃体内注射AAV 2-sFasL载体
可以预防青光眼的发展,而发病后注射AAV 2-sFasL可以逆转
功能缺陷总之,这些数据表明,FasL是患有糖尿病的患者的重要治疗靶点。
青光眼然而,一些关键问题仍然没有答案,将由拟议的3
具体目的:(目的1)在肿瘤的发生和进展过程中,何时以及如何抑制FasL裂解,
青光眼及ADAM 10和TIMP 1如何调节FasL裂解?(Aim(2)在多大程度上,
星形胶质细胞和/或RGCs表达的Fas参与青光眼的发展?和
(Aim(3)sFasL能否直接与Fas结合,引发保护性基因表达程序?我们的研究策略
将涉及公认的和新颖的实验工具,包括(a)分选酶标记的FasL小鼠(由Dr.
Ploegh},这将极大地促进我们监测眼睛中mFasL与sFasL蛋白水平的能力,{B} Fas-弯曲
与RGC和星形胶质细胞/穆勒特异性ere-deleter系杂交的小鼠,这将使我们能够确定
(c)通过融合Fas+ CD 4 + CD 4 + T细胞制备的同种异体(四亲)嵌合小鼠;
和Fasn·9胚胎,这将使我们能够区分FasL参与的直接和间接影响,
和{d} AAV 2-sFasL载体,其将允许我们确定sFasL是否独立于
mFasL。从拟议的研究中获得的机制见解可能会揭示改进的策略,
在患有青光眼和其他眼部疾病的患者中有效操纵Fas/FasL相互作用。
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:
10867990 - 财政年份:2022
- 资助金额:
$ 61.96万 - 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:
$ 61.96万 - 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:
$ 61.96万 - 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:
$ 61.96万 - 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:
$ 61.96万 - 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:
$ 61.96万 - 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:
8385057 - 财政年份:2012
- 资助金额:
$ 61.96万 - 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:
$ 61.96万 - 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:
$ 61.96万 - 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:
$ 61.96万 - 项目类别:
相似国自然基金
Epac1/2通过蛋白酶体调控中性粒细胞NETosis和Apoptosis在急性肺损伤中的作用研究
- 批准号:LBY21H010001
- 批准年份:2020
- 资助金额:0.0 万元
- 项目类别:省市级项目
基于Apoptosis/Ferroptosis双重激活效应的天然产物AlbiziabiosideA的抗肿瘤作用机制研究及其结构改造
- 批准号:81703335
- 批准年份:2017
- 资助金额:20.0 万元
- 项目类别:青年科学基金项目
双肝移植后Apoptosis和pyroptosis在移植物萎缩差异中的作用和供受者免疫微环境变化研究
- 批准号:81670594
- 批准年份:2016
- 资助金额:58.0 万元
- 项目类别:面上项目
Serp-2 调控apoptosis和pyroptosis 对肝脏缺血再灌注损伤的保护作用研究
- 批准号:81470791
- 批准年份:2014
- 资助金额:73.0 万元
- 项目类别:面上项目
Apoptosis signal-regulating kinase 1是七氟烷抑制小胶质细胞活化的关键分子靶点?
- 批准号:81301123
- 批准年份:2013
- 资助金额:23.0 万元
- 项目类别:青年科学基金项目
APO-miR(multi-targeting apoptosis-regulatory miRNA)在前列腺癌中的表达和作用
- 批准号:81101529
- 批准年份:2011
- 资助金额:22.0 万元
- 项目类别:青年科学基金项目
放疗与细胞程序性死亡(APOPTOSIS)相关性及其应用研究
- 批准号:39500043
- 批准年份:1995
- 资助金额:9.0 万元
- 项目类别:青年科学基金项目
相似海外基金
Spatial Restriction of Apoptotic Machinery during Neuronal Apoptosis and Pruning
神经元凋亡和修剪过程中凋亡机制的空间限制
- 批准号:
10596657 - 财政年份:2021
- 资助金额:
$ 61.96万 - 项目类别:
Spatial Restriction of Apoptotic Machinery during Neuronal Apoptosis and Pruning
神经元凋亡和修剪过程中凋亡机制的空间限制
- 批准号:
10417219 - 财政年份:2021
- 资助金额:
$ 61.96万 - 项目类别:
Examining the contribution of apoptosis repressor with caspase recruitment domain (ARC) to the anti-apoptotic effect of endurance training in skeletal muscle
检查具有半胱天冬酶募集结构域 (ARC) 的凋亡抑制因子对骨骼肌耐力训练的抗凋亡作用的贡献
- 批准号:
441952-2013 - 财政年份:2015
- 资助金额:
$ 61.96万 - 项目类别:
Alexander Graham Bell Canada Graduate Scholarships - Doctoral
Examining the contribution of apoptosis repressor with caspase recruitment domain (ARC) to the anti-apoptotic effect of endurance training in skeletal muscle
检查具有半胱天冬酶募集结构域 (ARC) 的凋亡抑制因子对骨骼肌耐力训练的抗凋亡作用的贡献
- 批准号:
441952-2013 - 财政年份:2014
- 资助金额:
$ 61.96万 - 项目类别:
Alexander Graham Bell Canada Graduate Scholarships - Doctoral
Understanding the activation of pro-apoptotic Bcl-2 family proteins for the development of modulators of apoptosis
了解促凋亡 Bcl-2 家族蛋白的激活以开发凋亡调节剂
- 批准号:
nhmrc : 1059331 - 财政年份:2014
- 资助金额:
$ 61.96万 - 项目类别:
Project Grants
Examining the contribution of apoptosis repressor with caspase recruitment domain (ARC) to the anti-apoptotic effect of endurance training in skeletal muscle
检查具有半胱天冬酶募集结构域 (ARC) 的凋亡抑制因子对骨骼肌耐力训练的抗凋亡作用的贡献
- 批准号:
441952-2013 - 财政年份:2013
- 资助金额:
$ 61.96万 - 项目类别:
Postgraduate Scholarships - Doctoral
Apoptotic Osteocytes Promote Chondrocyte Apoptosis via Soluble Factors
凋亡骨细胞通过可溶性因子促进软骨细胞凋亡
- 批准号:
251802 - 财政年份:2012
- 资助金额:
$ 61.96万 - 项目类别:
Studentship Programs
Defining the mechanism(s) by which the cellular inhibitor of apoptosis protein 2 (cIAP2) contributes to early stage atherosclerosis development by directly promoting the participation of key apoptotic pathways within lesion-associated macrophages
确定凋亡蛋白细胞抑制剂 2 (cIAP2) 通过直接促进病变相关巨噬细胞内关键凋亡途径的参与来促进早期动脉粥样硬化发展的机制
- 批准号:
191299 - 财政年份:2009
- 资助金额:
$ 61.96万 - 项目类别:
Operating Grants
ATP release during apoptosis and its relevance to apoptotic cell clearance
凋亡过程中 ATP 释放及其与凋亡细胞清除的相关性
- 批准号:
8075522 - 财政年份:2009
- 资助金额:
$ 61.96万 - 项目类别:
ATP release during apoptosis and its relevance to apoptotic cell clearance
凋亡过程中 ATP 释放及其与凋亡细胞清除的相关性
- 批准号:
7676912 - 财政年份:2009
- 资助金额:
$ 61.96万 - 项目类别: