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Biochemical characterization of a novel Fragile X Mental Retardation Protein nuclease function

Award Number: R15GM127307
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2005
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Biochemical characterization of a novel Fragile X Mental Retardation Protein nuclease function - Project Summary Fragile X mental retardation syndrome is the most common form of inherited mental impairement, affecting ~ 1 in 4000 males and ~ 1 in 6000 females. The syndrome is caused by the loss of a normal cellular protein, named the fragile X mental retardation protein (FMRP), which is an RNA binding protein involved in the transport and translation regulation of specific messenger RNA (mRNA) targets. We have determined that FMRP has nuclease activity, being able to process precursor microRNAs (pre-miRNAs), potentially being involved in the mature miRNA biogenesis. The parental proposal, which will characterize this novel FMRP function, has the following specific aims: AIM I. Identification of the FMRP domain(s) responsible for its nuclease activity. Under this aim we will determine: (i) if the FMRP nuclease activity resides in one of his KH domains and identify the active site residues responsible for this activity by point mutations; (ii) if FMRP S500D has higher nuclease activity as compared with unphosphorylated FMRP due different dimerization properties and (iii) if the paralogs FXR1P and FXR2P, which share with FMRP the KH0, KH1 and KH2 domains, also have nuclease activity. AIM II. Biochemical characterization of the FMRP nuclease activity. Under this specific aim we will: (i) determine if FMRP and FMRP S500D cleave pre-miRNAs into mature miRNAs; (ii) determine if they have additional substrates such as RNA perfect duplex, RNA single strand, RNA G quadruplex, DNA-RNA hybrid duplex, DNA duplex; (iii) characterize the kinetics of their nuclease activity. Similar experiments will pe performed to test the nuclease activity of the FMRP paralogs FXR1P and FXR2P. AIM III. Investigation of the FMRP interactions with the SARS-CoV-2 3’-UTR genome and of the potential role played by its nuclease activity in this viral system. Under this aim we will investigate if FMRP and FMRP S500D, as well as FXR1P and FXR2P interact with the SARS-CoV-2 3’-UTR genome, cleaving conserved stem- loops either to potentially yield viral miRNAs or functioning in the antiviral host response. Fluorescence spectroscopy will be used in all three specific aims of the parent R15 proposal, with the requested Fluorolog-QM-75-11-C spectrofluorometer and accessories being essential for the success of the proposed experiments.


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 = $0 )
2024	2023	DUQUESNE UNIVERSITY OF THE HOLY SPIRIT	600 FORBES AVENUE	PITTSBURGH	PA	15282	ALLEGHENY	USA	Biomedical Research and Research Training	001	5	8/1/2024	SUPPLEMENT FOR EXPANSION	$0
2024	2021	DUQUESNE UNIVERSITY OF THE HOLY SPIRIT	600 FORBES AVENUE	PITTSBURGH	PA	15282	ALLEGHENY	USA	Biomedical Research and Research Training	000	5	7/31/2024	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $100,000 )
2023	2023	DUQUESNE UNIVERSITY OF THE HOLY SPIRIT	600 FORBES AVENUE	PITTSBURGH	PA	15282	ALLEGHENY	USA	Biomedical Research and Research Training	000	5	8/14/2023	SUPPLEMENT FOR EXPANSION	$100,000
														Subtotal = $100,000

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	DUQUESNE UNIVERSITY OF THE HOLY SPIRIT	600 FORBES AVE	PITTSBURGH	PA	15282	ALLEGHENY	USA	Biomedical Research and Research Training	000	5	11/18/2021	COMPETING CONTINUATION	$0
2022	2021	DUQUESNE UNIVERSITY OF THE HOLY SPIRIT	600 FORBES AVENUE	PITTSBURGH	PA	15282	ALLEGHENY	USA	Biomedical Research and Research Training	002	5	3/2/2022	COMPETING CONTINUATION	$32,046
2022	2017	DUQUESNE UNIVERSITY OF THE HOLY SPIRIT	600 FORBES AVENUE	PITTSBURGH	PA	15282	ALLEGHENY	USA	Biomedical Research and Research Training	001	4	3/2/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$32,046
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $414,000 )
2021	2021	DUQUESNE UNIVERSITY OF THE HOLY SPIRIT	600 FORBES AVE	PITTSBURGH	PA	15282	ALLEGHENY	USA	Biomedical Research and Research Training	002	5	9/20/2021	COMPETING CONTINUATION	$414,000
2021	2017	DUQUESNE UNIVERSITY OF THE HOLY SPIRIT	600 FORBES AVE STE 205	PITTSBURGH	PA	15219	ALLEGHENY	USA	Biomedical Research and Research Training	000	4	6/23/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2021	2017	DUQUESNE UNIVERSITY OF THE HOLY SPIRIT	600 FORBES AVE	PITTSBURGH	PA	15282	ALLEGHENY	USA	Biomedical Research and Research Training	001	4	9/10/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $414,000

Issue Date FY: 2017 ( Subtotal = $414,000 )
2017	2017	DUQUESNE UNIVERSITY OF THE HOLY SPIRIT	600 FORBES AVE STE 205	PITTSBURGH	PA	15219	ALLEGHENY	USA	Biomedical Research and Research Training	000	4	8/28/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$414,000
														Subtotal = $414,000

Grand Total All Awards = $928,000

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Biochemical characterization of a novel Fragile X Mental Retardation Protein nuclease function

Award Number: R15GM127307

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2005

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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