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

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(Fasl)首次被鉴定为一种诱导死亡受体配体

项目成果

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MEREDITH GREGORY-KSANDER其他文献

MEREDITH GREGORY-KSANDER的其他文献

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{{ 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:

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