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Fas Ligand Cleavage regulates ocular homeostasis and glaucoma

Award Number: R01EY032762
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2022
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Fas Ligand Cleavage regulates ocular homeostasis and glaucoma - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $0 )
2026	2025	SCHEPENS EYE RESEARCH INSTITUTE, INC., THE	20 STANIFORD ST	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	4	11/24/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $588,524 )
2025	2025	SCHEPENS EYE RESEARCH INSTITUTE, INC., THE	20 STANIFORD ST	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	4	1/17/2025	NON-COMPETING CONTINUATION	$588,524
														Subtotal = $588,524

Issue Date FY: 2024 ( Subtotal = $600,249 )
2024	2024	SCHEPENS EYE RESEARCH INSTITUTE, INC., THE	20 STANIFORD ST	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	3	1/30/2024	NON-COMPETING CONTINUATION	$600,249
														Subtotal = $600,249

Issue Date FY: 2023 ( Subtotal = $643,824 )
2023	2023	SCHEPENS EYE RESEARCH INSTITUTE INC	20 STANIFORD ST	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	2	1/27/2023	NON-COMPETING CONTINUATION	$600,249
2023	2023	SCHEPENS EYE RESEARCH INSTITUTE, INC., THE	20 STANIFORD ST	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	001	2	8/23/2023	SUPPLEMENT FOR EXPANSION	$43,575
														Subtotal = $643,824

Issue Date FY: 2022 ( Subtotal = $619,633 )
2022	2022	SCHEPENS EYE RESEARCH INSTITUTE, INC., THE	20 STANIFORD ST	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	1	1/13/2022	NEW	$619,633
														Subtotal = $619,633

Grand Total All Awards = $2,452,230

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Fas Ligand Cleavage regulates ocular homeostasis and glaucoma

Award Number: R01EY032762

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 02/01/2022

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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