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Role of Primary Sensory Neuron CaMKII Signaling in Regulation of Pain

Award Number: R01NS128410
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: 05/01/2024
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Role of Primary Sensory Neuron CaMKII Signaling in Regulation of Pain - Summary/Abstract Chronic pain is a major public health challenge that is inadequately addressed. While opioids afford acute relief, their chronic use often leads to addiction and intolerable side-effects in patients. We and others have shown that dorsal root ganglion (DRG) field stimulation blocks pain in patients and pre-clinical models, which provides an opportunity to directly identify the underlying mechanisms of neuropathic pain, and hopefully to find novel non- opioid approaches to reduce pain. One protein we have identified to be a valid target is the calcium/calmodulin (Ca2+/CaM)-dependent protein kinase (CaMKII), a critical regulator of the analgesic effects of DRG stimulation. CaMKII is able to orchestrate diverse cellular functions to match required changes in excitable cell activity. Knowledge on the role of CaMKII in regulating peripheral nervous system and primary sensory neuron function is limited. Prior studies examining its role in pain have consistently associated it with mechanisms generating pain rather than analgesia, based on experiments exposing both the peripheral nervous system and the central nervous system to pharmacological inhibitors of CaMKII signaling. In contrast, our promising initial findings ex- amining CaMKII signaling specifically in peripheral sensory neurons, i.e., those with their cell bodies in the DRGs, indicate that painful conditions induced in preclinical models are associated with deficient sensory neuron CaMKII signaling. Selective inhibition of peripheral sensory neuron CaMKII at the level of the DRG produces hyperalgesia, while amplification of sensory neuron CaMKII signaling by molecular or electrical neuromodulation approaches produces potent analgesia. We have developed viral approaches highly suited for selectively tar- geting CaMKII in primary sensory neurons, and are proposing the following Aims to test the hypothesis that reduced activity of CaMKII in peripheral sensory neurons drives the maintenance of chronic pain, and increasing activity of CaMKII in DRG will alleviate chronic pain. Specifically, Aim 1. Establish the role of peripheral sensory neuron CaMKII activity in suppressing pain. Aim 2. Identify the anatomic site of action for sensory neuron CaMKII analgesia. Aim 3. Determine molecular mechanisms of CaMKII inactivation in animal and cell models of pain. Completion of the proposed project will generate new insights on how sensory neuron CaMKII regulates the development of neuropathic and osteoarthritic pain, along with proof-of-concept foundations for developing novel opioid-free treatments based on selective reversal of chronic pain-induced down-regulated CaMKII activity.


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 = $630,092 )
2025	2025	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	3	5/2/2025	NON-COMPETING CONTINUATION	$630,092
2025	2024	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	1/17/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$455,050
2025	2023	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	1/17/2025	NEW	-$455,050
														Subtotal = $630,092

Issue Date FY: 2024 ( Subtotal = $629,263 )
2024	2024	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	6/26/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$629,263
2024	2023	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	6/26/2024	NEW	$0
														Subtotal = $629,263

Issue Date FY: 2023 ( Subtotal = $621,180 )
2023	2023	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	5/30/2023	NEW	$621,180
														Subtotal = $621,180

Grand Total All Awards = $1,880,535

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Role of Primary Sensory Neuron CaMKII Signaling in Regulation of Pain

Award Number: R01NS128410

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: 05/01/2024

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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