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Translation Control of Pain Plasticity

Award Number: R01NS065926
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: 03/15/2010
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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Translation Control of Pain Plasticity - In neurons, synaptic and intrinsic plasticity is dependent on the regulated control of mRNA translation. Over the past decade our work has focused on how translation regulation signaling is involved in neuronal plasticity that drives chronic pain. Our findings demonstrate that inflammatory and neuropathic injuries stimulate translation regulation signaling pathways in dorsal root ganglion (DRG) nociceptors, neurons that detect injurious or potentially injurious stimuli. The result of activation of these pathways is increased excitability of nociceptors, behavioral signs of ongoing pain and sensitization to mechanical and thermal stimulation. This body of work, supports the idea that therapeutics targeting translation regulation signaling pathways can be used for the efficacious treatment of chronic pain. Our overarching hypothesis for this continuing project is that MNK1 activation in nociceptors is the key regulatory factor for the translation of a subset of mRNAs that encode proteins that augment the excitability of nociceptors causing enhanced pain phenotypes. We will test this hypothesis using new transgenic mouse lines, cell type-specific translating ribosome affinity purification (TRAP), highly specific inhibitors of MNK1/2 and new generation inhibitors that are specific for MNK1. Our preliminary data indicates that the key MNK isoform for nociceptive behavioral plasticity is MNK1. Based on our electrophysiology experiments we hypothesize that the site of action for this kinase is in DRG neurons. Our first specific aim will test the hypothesis that MNK1 expression in nociceptors is a key driver of behavioral expression of chronic pain. We have created a TRAP line that expresses L10a-tagged ribosomes in neurons that express the Scn10a gene (Scn10aTRAP). In our second specific aim we will examine how translation of specific mRNAs is regulated in preclinical neuropathic pain models with and without genetic or pharmacological manipulations of MNK-eIF4E signaling. This will yield unprecedented molecular insight into plasticity-driven changes in gene expression in nociceptors in neuropathic pain. The third specific aim will focus on pharmacologically or genetically targeting mechanisms discovered using approaches in aims 1 and 2. For instance, our TRAP approach captures translational upregulation of the Mrgrpd receptor in a neuropathic model. We will use knockout mice to investigate the role of this receptor in sensory neuron excitability in neuropathic pain. The proposed specific aims will highlight a key regulatory pathway for neuropathic pain and give new insight into novel therapeutic targets for neuropathic pain.


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 = -$94,867 )
2025	2023	UNIVERSITY OF TEXAS AT DALLAS	800 WEST CAMPBELL RD.	RICHARDSON	TX	75080	DALLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	13	6/4/2025	NON-COMPETING CONTINUATION	-$81,027
2025	2023	UNIVERSITY OF TEXAS AT DALLAS	800 WEST CAMPBELL RD.	RICHARDSON	TX	75080	DALLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	13	6/4/2025	SUPPLEMENT FOR EXPANSION	-$13,840
														Subtotal = -$94,867

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	UNIVERSITY OF TEXAS AT DALLAS	800 WEST CAMPBELL RD.	RICHARDSON	TX	75080	DALLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	13	2/1/2024	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $629,124 )
2023	2023	UNIVERSITY OF TEXAS AT DALLAS	800 WEST CAMPBELL RD.	RICHARDSON	TX	75080	DALLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	13	2/27/2023	NON-COMPETING CONTINUATION	$537,341
2023	2023	UNIVERSITY OF TEXAS AT DALLAS	800 WEST CAMPBELL RD.	RICHARDSON	TX	75080	DALLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	13	3/2/2023	SUPPLEMENT FOR EXPANSION	$91,783
														Subtotal = $629,124

Issue Date FY: 2022 ( Subtotal = $629,124 )
2022	2022	UNIVERSITY OF TEXAS AT DALLAS	800 W CAMPBELL RD	RICHARDSON	TX	75080	DALLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	12	7/6/2022	SUPPLEMENT FOR EXPANSION	$91,783
2022	2022	UNIVERSITY OF TEXAS AT DALLAS	800 W CAMPBELL RD	RICHARDSON	TX	75080	DALLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	12	1/25/2022	NON-COMPETING CONTINUATION	$483,609
2022	2022	UNIVERSITY OF TEXAS AT DALLAS	800 W CAMPBELL RD	RICHARDSON	TX	75080	DALLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	12	3/24/2022	NON-COMPETING CONTINUATION	$53,732
														Subtotal = $629,124

Issue Date FY: 2021 ( Subtotal = $537,341 )
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	11	2/18/2021	NON-COMPETING CONTINUATION	$537,341
														Subtotal = $537,341

Issue Date FY: 2020 ( Subtotal = $537,341 )
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	10	3/25/2020	NON-COMPETING CONTINUATION	$537,341
														Subtotal = $537,341

Issue Date FY: 2019 ( Subtotal = $550,591 )
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	002	9	6/20/2019	COMPETING CONTINUATION	$35,970
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	9	2/20/2019	COMPETING CONTINUATION	$550,591
2019	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	8	6/20/2019	NON-COMPETING CONTINUATION	-$35,970
														Subtotal = $550,591

Issue Date FY: 2018 ( Subtotal = $331,097 )
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	8	4/30/2018	NON-COMPETING CONTINUATION	$33,110
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	8	1/8/2018	NON-COMPETING CONTINUATION	$297,987
														Subtotal = $331,097

Issue Date FY: 2017 ( Subtotal = $331,097 )
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	7	1/13/2017	NON-COMPETING CONTINUATION	$297,987
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	001	7	7/10/2017	NON-COMPETING CONTINUATION	$33,110
														Subtotal = $331,097

Issue Date FY: 2016 ( Subtotal = $331,097 )
2016	2016	UNIVERSITY OF TEXAS AT DALLAS	P.O. BOX 830688	RICHARDSON	TX	75083	DALLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	1/27/2016	NON-COMPETING CONTINUATION	$33,110
2016	2016	UNIVERSITY OF TEXAS AT DALLAS	P.O. BOX 830688	RICHARDSON	TX	75083	DALLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	1/5/2016	NON-COMPETING CONTINUATION	$297,987
														Subtotal = $331,097

Issue Date FY: 2015 ( Subtotal = $344,347 )
2015	2015	UNIVERSITY OF TEXAS AT DALLAS	P.O. BOX 830688	RICHARDSON	TX	75083	DALLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	1/29/2015	COMPETING CONTINUATION	$344,347
														Subtotal = $344,347

Issue Date FY: 2014 ( Subtotal = $0 )
2014	2013	UNIVERSITY OF ARIZONA	POST OFFICE BOX 3308	TUCSON	AZ	85722		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	5/14/2014	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2013 ( Subtotal = $369,047 )
2013	2013	UNIVERSITY OF ARIZONA	POST OFFICE BOX 3308	TUCSON	AZ	85722		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	1/17/2013	NON-COMPETING CONTINUATION	$344,189
2013	2013	UNIVERSITY OF ARIZONA	POST OFFICE BOX 3308	TUCSON	AZ	85722		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	5/23/2013	NON-COMPETING CONTINUATION	$24,858
														Subtotal = $369,047

Issue Date FY: 2012 ( Subtotal = $381,855 )
2012	2012	UNIVERSITY OF ARIZONA	POST OFFICE BOX 3308	TUCSON	AZ	85722		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	3/1/2012	NON-COMPETING CONTINUATION	$381,855
														Subtotal = $381,855

Issue Date FY: 2011 ( Subtotal = $361,450 )
2011	2011	UNIVERSITY OF ARIZONA	POST OFFICE BOX 3308	TUCSON	AZ	85722		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	6/7/2011	NON-COMPETING CONTINUATION	$26,190
2011	2011	UNIVERSITY OF ARIZONA	POST OFFICE BOX 3308	TUCSON	AZ	85722		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	2	7/11/2011	SUPPLEMENT FOR EXPANSION	$40,626
2011	2011	UNIVERSITY OF ARIZONA	POST OFFICE BOX 3308	TUCSON	AZ	85722		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	3/7/2011	NON-COMPETING CONTINUATION	$294,634
														Subtotal = $361,450

Issue Date FY: 2010 ( Subtotal = $327,225 )
2010	2010	UNIVERSITY OF ARIZONA	POST OFFICE BOX 3308	TUCSON	AZ	85722		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/5/2010	NEW	$327,225
														Subtotal = $327,225

Grand Total All Awards = $5,565,869

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Translation Control of Pain Plasticity

Award Number: R01NS065926

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: 03/15/2010

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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