Thursday, November 21, 2024 11/21/2024

Functional analysis of SBP2 and selenocysteine incorporation

Award Number: R01GM077073
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Abstract Selenium is an essential trace element that is incorporated into 25 human proteins as the amino acid selenocysteine (Sec). The proteins that contain Sec (selenoproteins) are essential for many cellular functions including combatting oxidative stress, thyroid hormone production and protein folding. Sec is incorporated at specific UGA codons that would otherwise signal translation termination. A specialized set of factors are known to be required for Sec incorporation: a specialized elongation factor that delivers the Sec- tRNASec to the ribosome and unique RNA binding proteins that bind to a Sec insertion sequence (SECIS) in selenoprotein mRNA 3' UTRs. This SECIS-protein complex signals the ribosome to incorporate Sec instead of translation termination. Our prior work has provided molecular characterization of each of the required factors, but the mechanism by which they interact with each other and other cellular components to allow Sec incorporation remains unknown. We provide preliminary evidence that the processive incorporation of 10 Sec residues into the selenium transport protein Selenoprotein P (SELENOP) requires a unique mechanism and additional factors. The overall goals for this proposal are to determine the mechanism by which SECIS binding proteins promote single and multiple Sec incorporation events. We propose to marry our vast library of molecular tools from prior work with new model systems including the first use of a genetically modified zebrafish system to study Sec incorporation as well as CRISPR/Cas9 edited cell lines. All vertebrates possess two SECIS binding proteins encoded by separate genes: SECISBP2 (SBP2) and SECISBP2L. While the mechanism of action for SBP2 is coming into focus, the role for SECISBP2L in Sec incorporation has not been deciphered. Our preliminary data shows that SECISBP2L is essential for the production of a specific 50 kDa selenoprotein, likely SEPHS2, during early development. As such, we have established three model systems to study the synthesis of SELENOP: in vitro translation, expression in transfected mammalian cells and a zebrafish system that will allow unprecedented access to the role of selenoprotein function during development. These are also leveraged and combined with structural biology and transcriptomics to determine how synthesis of the entire selenoproteome is regulated by SECIS binding proteins. In this proposal we propose to 1) Decipher the mechanism by which SECIS elements and SECIS binding proteins enable processive Sec incorporation into the selenium transport protein, SELENOP; 2) Determine the mechanism of SBP2-independent Sec incorporation and the role of SECIS binding proteins in responding to cellular stress; 3) Utilize a zebrafish model system to determine the function of SECISBP2L and the regulation of selenoprotein synthesis by oxidative stress. The successful completion of these aims will bring us significantly closer to our long term goal of developing reagents that will permit selective activation or inhibition of selenoprotein synthesis in vivo.


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 = -$59,290 )
2024	2022	RUTGERS, THE STATE UNIVERSITY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Biomedical Research and Research Training	001	17	8/7/2024	SUPPLEMENT FOR EXPANSION	-$17,319
2024	2022	RUTGERS, THE STATE UNIVERSITY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Biomedical Research and Research Training	000	17	8/7/2024	NON-COMPETING CONTINUATION	-$41,971
														Subtotal = -$59,290

Issue Date FY: 2022 ( Subtotal = $527,954 )
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Biomedical Research and Research Training	000	17	1/14/2022	NON-COMPETING CONTINUATION	$336,363
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Biomedical Research and Research Training	002	17	6/20/2022	SUPPLEMENT FOR EXPANSION	$144,013
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Biomedical Research and Research Training	001	17	6/7/2022	SUPPLEMENT FOR EXPANSION	$10,205
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Biomedical Research and Research Training	003	17	7/27/2022	NON-COMPETING CONTINUATION	$37,373
														Subtotal = $527,954

Issue Date FY: 2021 ( Subtotal = $373,736 )
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Biomedical Research and Research Training	001	16	2/12/2021	NON-COMPETING CONTINUATION	$37,373
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Biomedical Research and Research Training	000	16	1/26/2021	NON-COMPETING CONTINUATION	$336,363
														Subtotal = $373,736

Issue Date FY: 2020 ( Subtotal = $420,924 )
2020	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Biomedical Research and Research Training	000	15	2/6/2020	NON-COMPETING CONTINUATION	$336,363
2020	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Biomedical Research and Research Training	004	15	8/18/2020	SUPPLEMENT FOR EXPANSION	$47,188
2020	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Biomedical Research and Research Training	003	15	3/4/2020	NON-COMPETING CONTINUATION	$37,373
2020	2019	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Biomedical Research and Research Training	002	14	2/21/2020	COMPETING CONTINUATION	$70,158
2020	2018	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Biomedical Research and Research Training	001	13	2/21/2020	NON-COMPETING CONTINUATION	-$70,158
														Subtotal = $420,924

Issue Date FY: 2019 ( Subtotal = $468,440 )
2019	2019	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Biomedical Research and Research Training	002	14	8/2/2019	SUPPLEMENT FOR EXPANSION	$80,000
2019	2019	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Biomedical Research and Research Training	001	14	4/5/2019	COMPETING CONTINUATION	$388,440
2019	2018	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Biomedical Research and Research Training	000	13	4/2/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $468,440

Issue Date FY: 2018 ( Subtotal = $314,475 )
2018	2018	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Biomedical Research and Research Training	000	13	3/8/2018	NON-COMPETING CONTINUATION	$283,027
2018	2018	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Biomedical Research and Research Training	001	13	5/18/2018	NON-COMPETING CONTINUATION	$31,448
														Subtotal = $314,475

Issue Date FY: 2017 ( Subtotal = $314,475 )
2017	2017	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Biomedical Research and Research Training	000	12	4/17/2017	NON-COMPETING CONTINUATION	$283,027
2017	2017	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Biomedical Research and Research Training	001	12	6/7/2017	NON-COMPETING CONTINUATION	$31,448
														Subtotal = $314,475

Issue Date FY: 2016 ( Subtotal = $314,475 )
2016	2016	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Biomedical Research and Research Training	000	11	3/16/2016	NON-COMPETING CONTINUATION	$314,475
														Subtotal = $314,475

Issue Date FY: 2015 ( Subtotal = $405,300 )
2015	2015	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Biomedical Research and Research Training	002	10	7/24/2015	SUPPLEMENT FOR EXPANSION	$0
2015	2015	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Biomedical Research and Research Training	001	10	6/15/2015	SUPPLEMENT FOR EXPANSION	$90,825
2015	2015	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Biomedical Research and Research Training	000	10	1/27/2015	COMPETING CONTINUATION	$314,475
														Subtotal = $405,300

Issue Date FY: 2014 ( Subtotal = $296,724 )
2014	2014	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Biomedical Research and Research Training	002	9	3/20/2014	NON-COMPETING CONTINUATION	$297,120
2014	2013	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Biomedical Research and Research Training	000	8	2/5/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$20,964
2014	2013	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Biomedical Research and Research Training	001	7	2/6/2014	NON-COMPETING CONTINUATION	$20,568
														Subtotal = $296,724

Issue Date FY: 2013 ( Subtotal = $285,949 )
2013	2013	Rutgers, The State Univ Biomedical & HEALTH Sciences	65 Davidson Road	Piscataway	NJ	08554		USA	Biomedical Research and Research Training	004	8	2/5/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$20,964
2013	2013	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Biomedical Research and Research Training	001	7	6/17/2013	NON-COMPETING CONTINUATION	$18,963
2013	2013	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Biomedical Research and Research Training	000	7	3/21/2013	NON-COMPETING CONTINUATION	$262,571
2013	2013	Rutgers, The State Univ Biomedical & HEALTH Sciences	65 Davidson Road	Piscataway	NJ	08554		USA	Biomedical Research and Research Training	003	8	8/16/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$266,419
2013	2013	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Biomedical Research and Research Training	005	7	2/6/2014	NON-COMPETING CONTINUATION	$20,568
2013	2013	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Biomedical Research and Research Training	002	7	8/15/2013	NON-COMPETING CONTINUATION	-$261,608
														Subtotal = $285,949

Issue Date FY: 2012 ( Subtotal = $298,975 )
2012	2012	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Biomedical Research and Research Training	001	6	7/9/2012	SUPPLEMENT FOR EXPANSION	$7,110
2012	2012	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Biomedical Research and Research Training	000	6	3/30/2012	NON-COMPETING CONTINUATION	$291,865
														Subtotal = $298,975

Issue Date FY: 2011 ( Subtotal = $291,980 )
2011	2011	UMDNJ, ROBERT WOOD JOHNSON MED SCH	335 GEO ST LIBERTY PLAZA 4 FL	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Biomedical Research and Research Training	000	5	3/28/2011	COMPETING CONTINUATION	$291,980
														Subtotal = $291,980

Issue Date FY: 2009 ( Subtotal = $265,810 ) (Continued on the next page)
Grand Total All Awards = $5,422,617

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Functional analysis of SBP2 and selenocysteine incorporation

Award Number: R01GM077073

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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