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Discovery and validation of a new long noncoding RNA as a novel target for neuropathic pain

Award Number: RF1NS113881
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: 09/30/2019
PERIOD OF PERFORMANCE END DATE: 08/31/2024

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Discovery and validation of a new long noncoding RNA as a novel target for neuropathic pain - Summary Chronic neuropathic pain is a major public issue due to its high incidence in the general population, the associated social burden and very limited efficacy of current treatment. Identification of new targets and mechanisms underlying this disorder is essential for the discovery of novel treatments and preventative tactics for better neuropathic pain management. We recently carried out a next generation RNA sequencing approach and identified a large, native, full-length long noncoding RNA (lncRNA) in mouse and human dorsal root ganglion (DRG). Because its expression is increased in injured DRG in response to peripheral nerve injury, but not to inflammation, we named it as nerve injury-specific lncRNA (NIS-lncRNA). NIS-lncRNA has two splice variants: variant 1 (V1) and V2. Our pilot work revealed that blocking the nerve injury-induced increase in the levels of DRG NIS-lncRNA V1 and V2 ameliorated neuropathic pain. Mimicking this increase elevated the expression of C-C chemokine ligand 2 (CCL2, a key player in neuropathic pain genesis) in the DRG and led to neuropathic pain-like symptoms in naive mice. These effects required the expression of DRG FUS (Fused in sarcoma), a DNA-binding protein that is required for transcription initiation. These pilot findings suggest that DRG NIS-lncRNA, as a therapeutic target, contributes to a peripheral mechanism underlying neuropathic pain through promotion of DRG FUS-controlled Ccl2 gene transcription. This proposal will validate NIS-lncRNA as a therapeutic target in neuropathic pain models. In Specific Aim 1, we will characterize the modified long-acting antisense oligonucleotides (ASOs) that specifically knock down V1 and V2 (V1 ASO and V2 ASO), respectively, delivered intrathecally for their in vivo stability and efficacy to reduce chronic constriction injury (CCI)-induced neuropathic pain. To better predict clinical applicability, we will also validate their efficacy in spinal nerve ligation-, paclitaxel (chemotherapy)- and streptozotocin (diabetic)-induced neuropathic pain. To confirm the role of NIS-lncRNA in neuropathic pain, we will examine the effect of genetic knockdown/knockout of DRG NIS-lncRNA through microinjection of AAV5-Cre into the DRG of NIS-lncRNAfl/fl mice or cross-breeding of the NIS-lncRNAfl/fl mice with conditional advillincre mice on CCI-induced pain hypersensitivity. In Specific Aim 2, we will determine how blocking the increased NIS-lncRNA in the injured DRG produces antinociceptive effects in neuropathic pain. We will validate the expression pattern of NIS-lncRNA in the DRG after CCI. We will examine whether blocking the CCI-induced increase in DRG NIS-lncRNA inhibits DRG CCL2 elevation, CCL2-mediated DRG neuronal hyper-excitability and spinal cord dorsal central sensitization after CCI. We will define whether CCI-induced increase in DRG NIS-lncRNA promotes the binding of FUS with the promoter of Ccl2 gene and subsequently increases FUS-controlled CCL2 expression in the injured DRG after CCI. In Specific Aim 3, we will collaborate with Dr. Davidson at the University of Cincinnati to validate the role of NIS- lncRNA in human DRG. We will verify the expression of NIS-lncRNA in human DRG, define its expression pattern, and examine its role in CCL2 expression and neuronal excitability in the viable human DRG neurons exposed to paclitaxel. Completing this proposal will advance neuropathic pain management and may provide a novel non-opioid target for this disorder.


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 = -$44,117 )
2025	2019	RUTGERS, THE STATE UNIVERSITY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	10/1/2024	NEW	-$44,117
														Subtotal = -$44,117

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2019	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	5/3/2024	NEW	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2019	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/1/2021	NEW	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = -$48,195 )
2020	2019	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	11/5/2019	NEW	-$48,195
														Subtotal = -$48,195

Issue Date FY: 2019 ( Subtotal = $3,512,402 )
2019	2019	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/24/2019	NEW	$3,512,402
														Subtotal = $3,512,402

Grand Total All Awards = $3,420,090

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Discovery and validation of a new long noncoding RNA as a novel target for neuropathic pain

Award Number: RF1NS113881

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: 09/30/2019

PERIOD OF PERFORMANCE END DATE: 08/31/2024

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