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Post transcriptional control of gene expression in the lens

Award Number: R01EY021505
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2011
PERIOD OF PERFORMANCE END DATE: 02/28/2025

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Post transcriptional control of gene expression in the lens - The eye lens is a transparent tissue that refracts and focuses light on the retina to allow clear vision. If the lens loses its transparency, vision is impaired, and the disease is termed “cataract”. Cataract is the major cause of blindness worldwide, commonly found in aged individuals (about half of Americans aged 80 or older develop cataract), but can also be present at birth or develop in early childhood – termed pediatric cataract. Genetic anomalies are estimated to account for about 25-50% of pediatric cataract cases, and the etiology of majority of these are unknown. Importantly, while the role of signaling and transcription factors in lens development and cataract have been well defined over the last few decades, that of proteins involved in post-transcriptional gene expression control is grossly understudied – indeed, only four such proteins have been characterized so far in the lens. Our efforts in characterizing these proteins have demonstrated that post-transcriptional regulatory mechanisms are critical for lens development, and their loss results in early onset cataract and eye defects. Identification of these factors was made possible by our novel bioinformatics approach iSyTE (integrated Systems Tool for Eye gene discovery), which is effective in identifying high-priority target genes linked to lens development and cataract. We have now used iSyTE to identify a new post-transcriptional regulator in the lens, namely, Elavl1 (Embryonic lethal abnormal vision (ELAV) like RNA-binding protein). The function of Elavl1 has not been examined in the lens. Therefore, we developed a new Elavl1-targeted lens-specific conditional knockout (KO) mouse model and find that Elavl1cKO mice exhibit early onset eye defects namely, cataract and microphthalmia. In this proposal, we will test the overarching hypothesis that Elavl1 mediates post-transcriptional gene expression control over key regulators of lens development, disruption of which causes cataract and microphthalmia. Specifically, we will address the following goals. (Aim 1) Characterize the pathogenesis of lens defects in Elavl1cKO mice and gain insights into the structural and molecular underpinning of these defects by comparative analysis of lens morphology, transcriptome and proteome. (Aim 2) Test the mechanism of Elavl1- mediated control of post-transcriptional gene expression in the lens. Specifically, we will investigate the molecular mechanism of Elavl1 function in control of the key lens development/differentiation transcription factors Pax6, c-Maf and Prox1 among other targets. Identify direct RNA targets of Elavl1 by RNA-immunoprecipitation followed by RNA-Sequencing. (Aim 3) Examine how Elavl1 and Celf1 coordinately mediate post-transcriptional control in the lens and integrate and analyze all the molecular, genomic and functional data generated above to derive Elavl1 and Celf1-regulatory networks in the lens. The expected overall impact of these innovative investigative approaches aimed at uncovering the mechanism of Elavl1 function is that it will continue to advance our knowledge of gene expression regulation in the lens at the post-transcriptional level while informing on the nature of RBP-based combinatorial control, in turn leading to identification of new targets linked to cataract.


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: 2024 ( Subtotal = $391,800 )
2024	2024	UNIVERSITY OF DELAWARE	220 HULLIHEN HALL	NEWARK	DE	19716	NEW CASTLE	USA	Vision Research	000	13	2/14/2024	NON-COMPETING CONTINUATION	$391,800
														Subtotal = $391,800

Issue Date FY: 2023 ( Subtotal = $391,800 )
2023	2023	UNIVERSITY OF DELAWARE	220 HULLIHEN HALL	NEWARK	DE	19716	NEW CASTLE	USA	Vision Research	000	12	3/13/2023	NON-COMPETING CONTINUATION	$391,800
														Subtotal = $391,800

Issue Date FY: 2022 ( Subtotal = $380,046 )
2022	2022	UNIVERSITY OF DELAWARE	220 HULLIHEN HALL	NEWARK	DE	19716	NEW CASTLE	USA	Vision Research	000	11	3/9/2022	NON-COMPETING CONTINUATION	$380,046
														Subtotal = $380,046

Issue Date FY: 2021 ( Subtotal = $391,800 )
2021	2021	UNIVERSITY OF DELAWARE	220 HULLIHEN HALL	NEWARK	DE	19716	NEW CASTLE	USA	Vision Research	002	10	9/3/2021	COMPETING CONTINUATION	$70,666
2021	2021	UNIVERSITY OF DELAWARE	220 HULLIHEN HALL	NEWARK	DE	19716	NEW CASTLE	USA	Vision Research	000	10	2/2/2021	COMPETING CONTINUATION	$391,800
2021	2020	UNIVERSITY OF DELAWARE	220 HULLIHEN HALL	NEWARK	DE	19716	NEW CASTLE	USA	Vision Research	001	9	9/3/2021	NON-COMPETING CONTINUATION	-$70,666
														Subtotal = $391,800

Issue Date FY: 2020 ( Subtotal = $390,000 )
2020	2020	UNIVERSITY OF DELAWARE	220 HULLIHEN HALL	NEWARK	DE	19716	NEW CASTLE	USA	Vision Research	000	9	2/11/2020	NON-COMPETING CONTINUATION	$390,000
														Subtotal = $390,000

Issue Date FY: 2019 ( Subtotal = $390,000 )
2019	2019	UNIVERSITY OF DELAWARE	220 HULLIHEN HALL	NEWARK	DE	19716	NEW CASTLE	USA	Vision Research	000	8	2/26/2019	NON-COMPETING CONTINUATION	$390,000
														Subtotal = $390,000

Issue Date FY: 2018 ( Subtotal = $390,000 )
2018	2018	UNIVERSITY OF DELAWARE	220 HULLIHEN HALL	NEWARK	DE	19716	NEW CASTLE	USA	Vision Research	001	7	6/4/2018	NON-COMPETING CONTINUATION	$39,000
2018	2018	UNIVERSITY OF DELAWARE	220 HULLIHEN HALL	NEWARK	DE	19716	NEW CASTLE	USA	Vision Research	000	7	2/20/2018	NON-COMPETING CONTINUATION	$351,000
														Subtotal = $390,000

Issue Date FY: 2017 ( Subtotal = $390,000 )
2017	2017	UNIVERSITY OF DELAWARE	220 HULLIHEN HALL	NEWARK	DE	19716	NEW CASTLE	USA	Vision Research	000	6	2/23/2017	NON-COMPETING CONTINUATION	$351,000
2017	2017	UNIVERSITY OF DELAWARE	220 HULLIHEN HALL	NEWARK	DE	19716	NEW CASTLE	USA	Vision Research	001	6	7/24/2017	NON-COMPETING CONTINUATION	$39,000
														Subtotal = $390,000

Issue Date FY: 2016 ( Subtotal = $390,000 )
2016	2016	UNIVERSITY OF DELAWARE	210 HULLIHEN HALL	NEWARK	DE	19716	NEW CASTLE	USA	Vision Research	000	5	2/26/2016	COMPETING CONTINUATION	$390,000
														Subtotal = $390,000

Issue Date FY: 2014 ( Subtotal = $421,589 )
2014	2014	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Vision Research	000	4	3/21/2014	NON-COMPETING CONTINUATION	$421,589
														Subtotal = $421,589

Issue Date FY: 2013 ( Subtotal = $454,092 )
2013	2013	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Vision Research	000	3	3/8/2013	NON-COMPETING CONTINUATION	$430,192
2013	2013	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Vision Research	001	3	6/6/2013	NON-COMPETING CONTINUATION	$23,900
														Subtotal = $454,092

Issue Date FY: 2012 ( Subtotal = $477,991 )
2012	2012	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Vision Research	000	2	3/16/2012	NON-COMPETING CONTINUATION	$477,991
														Subtotal = $477,991

Issue Date FY: 2011 ( Subtotal = $403,980 )
2011	2011	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Vision Research	000	1	3/14/2011	NEW	$403,980
														Subtotal = $403,980

Grand Total All Awards = $5,263,098

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Post transcriptional control of gene expression in the lens

Award Number: R01EY021505

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2011

PERIOD OF PERFORMANCE END DATE: 02/28/2025

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