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Compartmentalized cAMP signaling in reactive astrocytes

Award Number: R01EY033816
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2024
PERIOD OF PERFORMANCE END DATE: 04/30/2029
AWARD TERMINATION DATE: 05/29/2025

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Compartmentalized cAMP signaling in reactive astrocytes - PROJECT SUMMARY Glaucoma is the leading cause of irreversible blindness and along with other optic neuropathies is characterized by the loss of retinal ganglion cells (RGCs). Increased intraocular pressure (IOP) management is the current standard of care for glaucoma patients, but fails to stop the irreversible loss of RGCs and progressive visual dysfunction. Glaucomatous RGC death was recently found to be driven by reactive optic nerve head (ONH) astrocytes, suggesting targeting these (and other) glial populations in the retina may be a viable strategy to protect RGCs. We recently discovered nuclear and cytoplasmic pools of cAMP, dependent on expression of soluble adenylyl cyclase (sAC), and associated with the stress-induced cell cycle inhibitor p21Cip, differentially regulate reactive astrocyte proliferation, microglial/macrophage activation, and RGC survival after traumatic optic nerve injury. Here, using a newly developed and reversible model of glaucoma in mice, we will establish the molecular, cellular, and transcriptional mechanisms that confer specificity to neurotoxic and protective astrocyte reactivity regulated by compartmented cAMP, sAC, and p21Cip in ONH astrocytes and Muller glia. An exciting element of our proposal is the use of state-of-the-art single cell RNA sequencing and cut-and-tag assays to identify the transcriptional and (epi)genetic changes induced by compartmented cAMP manipulation, and link those changes to reactive phenotypes in astrocytes and downstream effects on RGC survival and microglial/macrophage infiltration. All of this will be accomplished using novel AAV viral vectors to specifically target ONH astrocytes and Muller glia. These experiments will lead to the discovery of new biological pathways that regulate glial reactivity in neurodegenerative disease, and serve in the development of gliotheraputics for the treatment of glaucoma and other optic neuropathies.


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 = $549,437 )
2026	2026	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Vision Research	000	3	5/13/2026	NON-COMPETING CONTINUATION	$549,437
														Subtotal = $549,437

Issue Date FY: 2025 ( Subtotal = $585,646 )
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Vision Research	001	2	5/14/2025	NON-COMPETING CONTINUATION	$544,574
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Vision Research	002	1	5/29/2025	TERMINATION	$0
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Vision Research	000	1	11/21/2024	SUPPLEMENT FOR EXPANSION	$41,072
														Subtotal = $585,646

Issue Date FY: 2024 ( Subtotal = $544,574 )
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Vision Research	000	1	8/15/2024	NEW	$544,574
														Subtotal = $544,574

Grand Total All Awards = $1,679,657

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Compartmentalized cAMP signaling in reactive astrocytes

Award Number: R01EY033816

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2024

PERIOD OF PERFORMANCE END DATE: 04/30/2029

AWARD TERMINATION DATE: 05/29/2025

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