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Retinoid Signaling and Homeostasis in the Eye

Award Number: R01EY034842
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2024
PERIOD OF PERFORMANCE END DATE: 12/31/2028

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Retinoid Signaling and Homeostasis in the Eye - SUMMARY This proposal describes experiments to investigate the role played by STRA6 in modulating transcription of genetic pathways in the RPE. Mutations in human STRA6 are associated with Matthew-Wood syndrome, whose symptoms include microphthalmia-anophthalmia, as well as pulmonary hypoplasia. STRA6 is found on the surface of many blood-tissue barrier epithelia, including the RPE. Though almost exclusively described as a retinoid transporter, STRA6 also is a cytokine signaling receptor, whose function in this role has only been studied in non-ocular tissues. This provokes exciting speculation into its role in the RPE of the eye: what molecular signaling is controlled by STRA6 in the RPE? How do the genes whose expression is modulated by STRA6 contribute to RPE function or survival? Which pathway(s) are important to maintain the health of the RPE, which sustains the photoreceptors? We will use zebrafish as a cone-rich model system to address these questions. Our proposed research has three Specific Aims: (1) to uncover molecular signaling important for RPE function whose expression is modulated by STRA6, (2) to dissect the contributions from individual signaling pathways to the RPE by making precise pathway-specific amino acid changes to STRA6, and (3) to inactivate genes whose expression is altered by STRA6 inactivation to understand their contribution to RPE function and survival. We have used CRISPR/Cas9 approaches to inactivate both STRA6 and its ligand RBP4 to profile their contribution to transcriptional modulation in the whole animal eye and in isolated human RPE culture. Together, our results will shed light on the under-appreciated role of STRA6 in RPE homeostasis and maintenance, while providing novel opportunities to develop treatment strategies to aid survival of RPE cells to prevent or combat retinal disease. This proposal directly addresses emerging needs outlined in “NEI Strategic Plan – Vision for the Future 2021-2025”. Specifically, we will i) address gaps in animal models, such as a model with a high density of cone photoreceptors; ii) explore strategies to treat complex disease such as modulating the expression of specific genes or gene editing; iii) examine the roles of redox biology and mitochondrial function in ocular health; and iv) identify ocular disease genes to develop new strategies, models, and tools for elucidating genetic and environmental interactions at the cellular and systems level, and thereby accelerate mechanistic understanding and therapy development.


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 = $390,000 )
2026	2026	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Vision Research	000	3	1/29/2026	NON-COMPETING CONTINUATION	$390,000
														Subtotal = $390,000

Issue Date FY: 2025 ( Subtotal = $390,000 )
2025	2025	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Vision Research	000	2	12/19/2024	NON-COMPETING CONTINUATION	$390,000
														Subtotal = $390,000

Issue Date FY: 2024 ( Subtotal = $374,880 )
2024	2024	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Vision Research	000	1	12/7/2023	NEW	$374,880
														Subtotal = $374,880

Grand Total All Awards = $1,154,880

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Retinoid Signaling and Homeostasis in the Eye

Award Number: R01EY034842

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2024

PERIOD OF PERFORMANCE END DATE: 12/31/2028

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