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microRNA-204 and microRNA-211 regulation of RPE phagocytosis

Award Number: F30EY033642
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 01/07/2022
PERIOD OF PERFORMANCE END DATE: 01/06/2027

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microRNA-204 and microRNA-211 regulation of RPE phagocytosis - PROJECT SUMMARY/ABSTRACT Age-related macular degeneration (AMD) is a disease that leads to the loss of visual acuity, resulting in a substantial medical and social burden. Many unique pathways lead to the pathogenesis of AMD. The retinal pigment epithelium (RPE) is a post-mitotic epithelial monolayer which sits directly adjacent to the photoreceptor outer segments (POS) and is responsible for the maintenance of photoreceptor health. Among its functions include the generation of 11-cis-retinal chromophore for phototransduction, nutrient delivery, and diurnal phagocytosis of spent POS. Degeneration and dysfunction in the RPE is linked to the subsequent decline in photoreceptors seen in diseases such as AMD and Leber’s congenital amaurosis. Therefore, understanding RPE dysfunction is critical to understanding overall retinal health, but regulation of these key RPE roles is still incompletely understood. Recent research has pointed to the important role of microRNA (miR) regulation of gene expression, and miRs are critical for ophthalmic development and homeostasis. Of these miRs, miR-204 and miR-211 are among the most highly expressed miRs in the RPE and have been shown to both maintain its epithelial properties and modulate endosomal/lysosomal processing. These two miRs share the same seed sequence and are hypothesized to regulate many of the same genes, and are themselves regulated by light and the circadian clock. Previous studies have implicated the expression of these miRs in the control of RPE phagocytosis, but this has not been fully tested in a RPE specific manner. Thus, this proposal will examine the role(s) of miR-204 and miR-211 in an RPE specific manner and test the hypothesis that these two miRs regulate RPE phagocytosis. To pursue these objectives, we have generated miR-204fl/fl and miR-211fl/fl double knock-in mice. Induction of recombination in double knock-in mice will be achieved by (1) crossing them with RPE65-ERT2-cre mice and inducing recombination in the resultant triple knock-in mice by intraperitoneal injection of tamoxifen; and (2) subretinal delivery of AAV1-CMV-cre-GFP. The miR double knockout mice will be aged and assessed for phenotypic, electrophysiological, and histological changes. RPE and retina from these mice will also be collected and analyzed through bulk and single cell RNA sequencing to examine changes in gene expression resulting from miR-204/miR-211 deletion. The direct target genes of these two miRs will be assessed through the application of Halo-enhanced Ago2 pulldown (HEAP). We will also perform the in vitro culture of double knock-in mouse RPE and challenge them with POS to assess their phagocytic capacity. Lastly, we will correlate the results for mouse RPE to analogous results for human RPE through the use of RPE cultures derived from induced pluripotent stem cells. Overall, these studies will seek to define the role(s) of miR-204 and miR-211 in the RPE, identify their regulated genes, and suggest further genes and pathways to target in the development of AMD therapeutics and diagnostics.


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 = $53,974 )
2025	2025	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Vision Research	000	4	12/6/2024	NON-COMPETING CONTINUATION	$53,974
														Subtotal = $53,974

Issue Date FY: 2024 ( Subtotal = $45,844 )
2024	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Vision Research	000	3	12/12/2023	NON-COMPETING CONTINUATION	$44,564
2024	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Vision Research	001	3	6/7/2024	NON-COMPETING CONTINUATION	$1,280
														Subtotal = $45,844

Issue Date FY: 2023 ( Subtotal = $43,836 )
2023	2023	UNIVERSITY OF CALIFORNIA, IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Vision Research	000	2	1/4/2023	NON-COMPETING CONTINUATION	$42,894
2023	2023	UNIVERSITY OF CALIFORNIA, IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Vision Research	001	2	3/8/2023	NON-COMPETING CONTINUATION	$942
														Subtotal = $43,836

Issue Date FY: 2022 ( Subtotal = $42,207 )
2022	2022	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Vision Research	001	1	1/7/2022	NEW	$0
2022	2022	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Vision Research	002	1	5/6/2022	NEW	$717
2022	2022	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Vision Research	003	1	5/27/2022	NEW	-$1
2022	2022	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Vision Research	000	1	1/7/2022	NEW	$41,491
														Subtotal = $42,207

Grand Total All Awards = $185,861

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microRNA-204 and microRNA-211 regulation of RPE phagocytosis

Award Number: F30EY033642

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 01/07/2022

PERIOD OF PERFORMANCE END DATE: 01/06/2027

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