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3’ End Regulation in Nociceptor Plasticity

Award Number: R01NS100788
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2022
PERIOD OF PERFORMANCE END DATE: 01/31/2023

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3’ End Regulation in Nociceptor Plasticity - Project Summary/Abstract Poorly managed pain creates an enormous burden on our healthcare system and produces tremendous human suffering. Following an injury, pain is caused by the production of inflammatory cytokines that induce changes in the excitability of nociceptor neurons. A better understanding of molecular mechanisms that facilitate nociceptor plasticity is vital for improved pain treatment. Post-transcriptional gene control has emerged as a dominant theme in pain induced plasticity. We focus on Poly(A) binding proteins (PABPs), a conserved family of 3’ end associated factors that regulate translation initiation and play prominent roles in development and memory. We will determine binding specificities for PABPs present in dorsal root ganglion (DRG) neurons using an unbiased next- generation sequencing approach. This information will be used to generate a novel class of chemically stabilized RNAs called specificity-derived competitive inhibitor oligonucleotides (SPOT-ONs). Unlike genome editing or RNA interference, SPOT-ONs are well tolerated and bypass the need for host-factors as they function as “decoys”. A major advantage of pharmacological inhibition as opposed to targeted gene disruption is the ability to simultaneously impair multiple homologues in a larger gene family. Our preliminary findings indicate that a bi- specific PABP SPOT-ON provides robust anti-hyperalgesic effects in vivo. Based on this finding, we hypothesize that PABPs are crucial mediators of plasticity in nociceptors. We describe preliminary development of SPOT- ONs which reduce protein synthesis in nociceptors and act specifically on poly(A)-mediated mRNA translation (Aim 1). We probe PABP mechanism of action through examination of localized translation and global identification of targets in nociceptors (Aim 2). Finally, we determine how PABP inhibition impacts nociceptor excitability and behavioral responses to injury (Aim 3).


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 = -$47 )
2024	2021	UNIVERSITY OF TEXAS AT DALLAS	800 WEST CAMPBELL RD.	RICHARDSON	TX	75080	DALLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	10/25/2023	NON-COMPETING CONTINUATION	$0
2024	2021	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	10/25/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$47
														Subtotal = -$47

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	UNIVERSITY OF TEXAS AT DALLAS	800 W CAMPBELL RD	RICHARDSON	TX	75080	DALLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	8/4/2022	NON-COMPETING CONTINUATION	-$145,997
2022	2021	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	8/11/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$145,997
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $403,215 )
2021	2021	UNIVERSITY OF TEXAS AT DALLAS	800 W CAMPBELL RD	RICHARDSON	TX	75080	DALLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	2/3/2021	NON-COMPETING CONTINUATION	$403,215
														Subtotal = $403,215

Issue Date FY: 2020 ( Subtotal = $403,215 )
2020	2020	UNIVERSITY OF TEXAS AT DALLAS	800 W CAMPBELL RD	RICHARDSON	TX	75080	DALLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	2/14/2020	NON-COMPETING CONTINUATION	$403,215
														Subtotal = $403,215

Issue Date FY: 2019 ( Subtotal = $403,215 )
2019	2019	UNIVERSITY OF TEXAS AT DALLAS	800 W CAMPBELL RD	RICHARDSON	TX	75080	DALLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	2/21/2019	NON-COMPETING CONTINUATION	$403,215
														Subtotal = $403,215

Issue Date FY: 2018 ( Subtotal = $403,215 )
2018	2018	UNIVERSITY OF TEXAS AT DALLAS	800 W CAMPBELL RD	RICHARDSON	TX	75080	DALLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	5/2/2018	NON-COMPETING CONTINUATION	$40,319
2018	2018	UNIVERSITY OF TEXAS AT DALLAS	800 W CAMPBELL RD	RICHARDSON	TX	75080	DALLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	1/8/2018	NON-COMPETING CONTINUATION	$362,896
														Subtotal = $403,215

Issue Date FY: 2017 ( Subtotal = $399,428 )
2017	2017	UNIVERSITY OF TEXAS AT DALLAS	800 W CAMPBELL RD	RICHARDSON	TX	75080	DALLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	1/26/2017	NEW	$399,428
														Subtotal = $399,428

Grand Total All Awards = $2,012,241

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3’ End Regulation in Nociceptor Plasticity

Award Number: R01NS100788

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2022

PERIOD OF PERFORMANCE END DATE: 01/31/2023

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