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AIBP-mediated neuroprotection in glaucomatous optic neuropathy

Award Number: R01EY034116
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2023
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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AIBP-mediated neuroprotection in glaucomatous optic neuropathy - Glaucoma is a leading cause of blindness worldwide and glia-driven neuroinflammation is a key element in the pathogenesis of glaucoma. Increasing evidence from clinical studies indicate that primary open-angle glaucoma is linked to single-nucleotide polymorphisms of toll-like receptor 4 (TLR4), mitochondrial cytochrome c oxidase subunit I of the oxidative phosphorylation (OXPHOS) complex-IV, ATP-binding cassette transporter A1 and Cholesterol-24S-hydroxylase, suggesting that TLR4-mediated neuroinflammation, cholesterol efflux and/or OXPHOS stress-mediated mitochondrial dysfunction play roles in glaucoma pathogenesis. ApoA-I binding protein (AIBP), encoded by the APOA1BP gene, is a secreted protein, which serves as a selective regulator of cellular cholesterol metabolism, targeting inflammatory cells via its binding to TLR4. Cholesterol depletion from inflammatory cells reduces lipid raft abundance and the membrane occupancy of receptors (such as TLR4) that mediate inflammatory signaling. Emerging evidence from our group showed that AIBP deficiency is associated with glia-driven inflammatory TLR4/interleukin-1β signaling axis and mitochondrial dysfunction in glaucomatous degeneration. In addition to protecting retinal ganglion cells (RGCs) against neuroinflammation, AIBP prevents RGC mitochondrial dysfunction in glaucomatous neurodegeneration. In preliminary studies, we demonstrated that AIBP expression is highly reduced in glaucomatous human and mouse RGCs and their axons, as well as Müller glia, and that amplification of retinal AIBP expression by adeno-associated virus delivery protects RGCs and preserves visual function in experimental glaucoma in vivo. In addition, treatment with recombinant AIBP protein promotes mitochondrial function in Müller glia against elevated pressure in vitro. Based on our previous and these findings, we propose to test the novel concept that AIBP controls retinal neuroinflammation and the RGC mitochondrial dysfunction, which lead to glaucomatous neurodegeneration, as well as to test the therapeutic potential of raising AIBP expression in the retina. The Specific Aims of this proposal are: (1) to define the mechanisms by which AIBP controls TLR4-lipid raft activation in inflammatory Müller glial cells; (2) to determine the protective mechanisms of AIBP amplification on mitochondrial network and bioenergetics in glaucomatous RGCs and Müller glial cells; and (3) to determine how therapeutic augmentation of AIBP expression impacts structural integrity and synapses linking RGCs and the central visual pathway. Our proposed studies will explore novel pathways which potentially link neuroinflammation regulation to elevated IOP-mediated mitochondrial function and cellular cholesterol metabolism. This work may also lead to the development of a new glaucoma therapy.


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: 2025 ( Subtotal = $676,867 )
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Vision Research	001	3	7/24/2025	SUPPLEMENT FOR EXPANSION	$54,055
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Vision Research	000	3	6/27/2025	NON-COMPETING CONTINUATION	$622,812
														Subtotal = $676,867

Issue Date FY: 2024 ( Subtotal = $669,380 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Vision Research	000	2	6/7/2024	NON-COMPETING CONTINUATION	$626,352
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Vision Research	001	2	6/10/2024	SUPPLEMENT FOR EXPANSION	$43,028
														Subtotal = $669,380

Issue Date FY: 2023 ( Subtotal = $644,896 )
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Vision Research	000	1	8/29/2023	NEW	$644,896
														Subtotal = $644,896

Grand Total All Awards = $1,991,143

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AIBP-mediated neuroprotection in glaucomatous optic neuropathy

Award Number: R01EY034116

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/30/2023

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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