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Molecular underpinnings of photoreceptor transcriptional regulation by CRX and NRL

Award Number: R01EY034455
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2023
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Molecular underpinnings of photoreceptor transcriptional regulation by CRX and NRL - Two key transcription factors, homeodomain protein CRX and basic leucine zipper protein NRL, are at the center of gene regulation during photoreceptor differentiation and homeostasis. CRX is essential for specifying commitment of postmitotic photoreceptor precursors to the development of photoreceptor cells, whereas NRL determines the rod cell fate. In orchestrating the transcriptional program of photoreceptor development, CRX and NRL cooperate functionally and physically via a direct protein-protein interaction. Defects in photoreceptor transcriptional regulation due to mutations in the genes encoding CRX and NRL cause severe retinal diseases including retinitis pigmentosa, cone-rod dystrophy, and Leber congenital amaurosis. Despite our advanced understanding of the biology and transcriptional networks of CRX and NRL, mechanistic insight into the functions and unique synergy of these transcription factors at the atomic level is lacking. In the proposed studies, we seek to determine the crystal and solution structures of the individual DNA-bound complexes of CRX and NRL, as well as the structure of the ternary CRX/NRL/DNA complex. Although mutations in these TFs have been identified, they have not been mechanistically linked to regulation of key genes. The mechanistic predictions from the structures on how disease-causing mutations in CRX and NRL may alter DNA-binding specificity at cis-regulatory elements will be validated in the follow-up assays, including high- throughput approaches such as Spec-seq. These studies will enhance our knowledge of the functions of CRX and NRL, define the molecular nature of their synergy, and allow us to delineate specific mechanisms whereby mutant CRX and NRL proteins cause retinal diseases. We hypothesize that ultimately the structures of CRX and NRL complexed with their cis-regulatory elements will enable targeted design of therapeutics to treat visual disorders via modulation of transcriptional activities at specific promoters.


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 = $388,750 )
2025	2025	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Vision Research	000	3	12/19/2024	NON-COMPETING CONTINUATION	$388,750
														Subtotal = $388,750

Issue Date FY: 2024 ( Subtotal = $388,750 )
2024	2024	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Vision Research	000	2	1/11/2024	NON-COMPETING CONTINUATION	$388,750
														Subtotal = $388,750

Issue Date FY: 2023 ( Subtotal = $388,750 )
2023	2023	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Vision Research	000	1	1/23/2023	NEW	$388,750
														Subtotal = $388,750

Grand Total All Awards = $1,166,250

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Molecular underpinnings of photoreceptor transcriptional regulation by CRX and NRL

Award Number: R01EY034455

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2023

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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