Friday, December 26, 2025 12/26/2025

Molecular Determinants of Synaptic Plasticity in Chronic Pain

Award Number: R01NS101880
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: 08/15/2017
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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Molecular Determinants of Synaptic Plasticity in Chronic Pain - Molecular Determinants of Synaptic Plasticity in Chronic Pain The long-term goal of our project is to identify the molecular and signaling mechanisms that govern synaptic plasticity under chronic pain conditions. Neuropathic pain remains a major therapeutic challenge, and neuronal plasticity at the spinal cord level is fundamentally important to the development of chronic neuropathic pain. N- methyl-D-aspartate receptors (NMDARs) are expressed in primary sensory neurons and their central terminals in the spinal dorsal horn. However, they are functionally inactive under normal conditions and become tonically activated to potentiate glutamatergic input to spinal dorsal horn neurons after nerve injury and chemotherapy- induced neuropathy. The molecular mechanisms regulating the synaptic activity and trafficking of NMDARs in the spinal dorsal horn remain poorly understood. Volume-regulated anion channels, which are formed by multiple different leucine-rich repeat-containing protein 8 (LRRC8) family members, are crucial to the regulation of cell volume. In our pilot studies, we found that LRRC8A was highly expressed in dorsal root ganglion (DRG) neurons. Also, traumatic nerve injury selectively downregulated LRRC8A, but not LRRC8B-LRRC8D, in the DRG. Furthermore, LRRC8A downregulation or conditional knockout in DRG neurons induces NMDAR-dependent pain hypersensitivity. Importantly, we discovered that LRRC8A physically interacted with NMDARs to control synaptic trafficking and activity of NMDARs. In this renewal application, we will specifically determine the roles of LRRC8A in the regulation of nociception and synaptic NMDARs at the spinal cord level in two neuropathic pain models. On the basis of our intriguing preliminary data, we propose to test the overall hypothesis that LRRC8A protein directly interacts with NMDARs and normally restrains the synaptic trafficking of NMDARs at the spinal cord level; nerve injury or chemotherapy diminishes LRRC8A expression and augments the synaptic expression and activity of NMDARs, leading to increased glutamatergic input to spinal dorsal horn neurons and chronic pain. We will apply several innovative and complementary approaches, including biochemical and cellular analyses, transgenic mice, and synaptic recordings to study how LRRC8A controls NMDARs and nociception at molecular, cellular, and behavioral levels. Our project will generate fundamental new information about the molecular basis of NMDAR-mediated synaptic plasticity in neuropathic pain. Findings from our project are expected to advance our knowledge of molecular mechanisms of nociceptive regulation and to guide the development of new strategies for treating chronic 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: 2026 ( Subtotal = $451,854 )
2026	2026	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	12/10/2025	NON-COMPETING CONTINUATION	$451,854
														Subtotal = $451,854

Issue Date FY: 2025 ( Subtotal = $451,854 )
2025	2025	THE UNIVERISTY OF TEXAS MD ANDERSON CANCER CENTER, A COMPONENT OF THE UNIVERISTY OF TEXAS SYSTEM	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	11/21/2024	NON-COMPETING CONTINUATION	$451,854
2025	2023	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	6	2/12/2025	COMPETING CONTINUATION	$69,949
2025	2021	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	2/12/2025	NON-COMPETING CONTINUATION	-$69,949
														Subtotal = $451,854

Issue Date FY: 2024 ( Subtotal = $486,998 )
2024	2024	THE UNIVERISTY OF TEXAS MD ANDERSON CANCER CENTER, A COMPONENT OF THE UNIVERISTY OF TEXAS SYSTEM	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	7	5/3/2024	NON-COMPETING CONTINUATION	$35,144
2024	2024	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	12/1/2023	NON-COMPETING CONTINUATION	$451,854
														Subtotal = $486,998

Issue Date FY: 2023 ( Subtotal = $502,059 )
2023	2023	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	11/30/2022	COMPETING CONTINUATION	$502,059
2023	2021	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	11/29/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $502,059

Issue Date FY: 2021 ( Subtotal = $427,286 )
2021	2021	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	7/9/2021	NON-COMPETING CONTINUATION	$427,286
														Subtotal = $427,286

Issue Date FY: 2020 ( Subtotal = $427,286 )
2020	2020	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	6/25/2020	NON-COMPETING CONTINUATION	$427,286
														Subtotal = $427,286

Issue Date FY: 2019 ( Subtotal = $427,286 )
2019	2019	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	7/5/2019	NON-COMPETING CONTINUATION	$427,286
														Subtotal = $427,286

Issue Date FY: 2018 ( Subtotal = $427,286 )
2018	2018	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	7/30/2018	NON-COMPETING CONTINUATION	$427,286
														Subtotal = $427,286

Issue Date FY: 2017 ( Subtotal = $427,286 )
2017	2017	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/3/2017	NEW	$427,286
														Subtotal = $427,286

Grand Total All Awards = $4,029,195

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Molecular Determinants of Synaptic Plasticity in Chronic Pain

Award Number: R01NS101880

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: 08/15/2017

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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