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Contribution of Local Translation to Nerve Injury-Induced Upregulation of Nav1.1 in Trigeminal Nerves

Award Number: F31NS125993
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 01/01/2022
PERIOD OF PERFORMANCE END DATE: 07/31/2024

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Contribution of Local Translation to Nerve Injury-Induced Upregulation of Nav1.1 in Trigeminal Nerves - PROJECT SUMMARY/ABSTRACT Chronic pain is both highly prevalent and a major cause of disability, affecting approximately 20.4% of the U.S. Despite this prevalence, there are still limited therapeutic options. These issues are particularly true for pain associated with trigeminal nerve injury. Recent comparative analyses support the presence of differences between trigeminal and somatic nerves regarding the response to injury, and also point to voltage-gated sodium channels (VGSCs) as a potential mechanism accounting for both the pain and differences in the efficacy of available therapeutic interventions. Furthermore, VGSCs accumulation at the site of nerve injury and changes in the relative density of subtypes in sensory neuron cell bodies have been implicated in the ongoing pain and hypersensitivity associated with peripheral nerve injury. There is no consensus in the literature as to which of the VGSC subtype(s) underlie action potential (AP) propagation along peripheral nerves, or which subtypes underlie AP propagation following injury. However, there is evidence that the redistribution of VGSC subunits along peripheral axons enables the nerve injury-induced pain and hypersensitivity, and therefore may serve as a viable therapeutic target. In this regard, we have preliminary data suggesting that trigeminal but not the somatic nerve injury is associated with an increase in functional NaV1.1 channels in trigeminal nerve axons that when blocked, reverse nerve injury-induced mechanical sensitivity. Two general mechanisms have been implicated in changes in axonal VGSC channels: protein trafficking and local translation of mRNA. While both mechanisms are possible, at least two lines of evidence suggest local translation may underly the nerve injury-induced increase in NaV1.1 in trigeminal axons. Thus, I hypothesize that the change in distribution of NaV1,1 in trigeminal nerves following injury is due to local translation, and that the increase in functional NaV1.1 axonal protein contributes to injury-induced hypersensitivity. To test this hypothesis, I will use a combination of techniques that will elucidate the contribution of local translation and protein trafficking to nerve-injury induced hypersensitivity in a series of experiments described under three specific aims involving anatomical and biochemical techniques (Aim 1), functional endpoints (Aim 2), and behavioral endpoints (Aim 3). Results from these aims will determine the basis for the nerve injury-induced increase in NaV1.1 in trigeminal nerve axons and their contribution to changes in nociception. Future studies will address the implications for these results for novel therapeutic approaches to the treatment of neuropathic pain. Along with the state-of-the-art facilities available, the highly collaborative environment in the Center for Neuroscience at the University of Pittsburgh will ensure the successful completion of the experiments proposed. These studies will also provide me with the technical and intellectual training required to become an independent investigator in the field of pain, while the commitment to diversity in the CNUP will allow me to pursue my career goal of promoting inclusion in science.


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 = -$8,748 )
2025	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	5/27/2025	NON-COMPETING CONTINUATION	-$8,748
														Subtotal = -$8,748

Issue Date FY: 2024 ( Subtotal = $31,550 )
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	5/10/2024	NON-COMPETING CONTINUATION	$830
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	1/10/2024	NON-COMPETING CONTINUATION	$30,720
														Subtotal = $31,550

Issue Date FY: 2023 ( Subtotal = $47,694 )
2023	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	12/23/2022	NON-COMPETING CONTINUATION	$46,752
2023	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	2/10/2023	NON-COMPETING CONTINUATION	$942
														Subtotal = $47,694

Issue Date FY: 2022 ( Subtotal = $46,752 )
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	11/27/2021	NEW	$0
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	1	6/2/2022	NEW	$716
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	11/27/2021	NEW	$46,036
														Subtotal = $46,752

Grand Total All Awards = $117,248

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Contribution of Local Translation to Nerve Injury-Induced Upregulation of Nav1.1 in Trigeminal Nerves

Award Number: F31NS125993

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 01/01/2022

PERIOD OF PERFORMANCE END DATE: 07/31/2024

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