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Neural immunoregulation of post-traumatic autoimmunity

Award Number: R01NS094438
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: 09/01/2016
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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Neural immunoregulation of post-traumatic autoimmunity - Chronic low back pain (LBP) and osteoarthritic (OA) joint pain are the most common causes of chronic disabling pain and despite extensive investigation the pathophysiology of these conditions remains undefined and there is considerable controversy regarding their clinical management. Clearly current hypotheses for the progression of tissue injury to painful disability have not, short of removing the painful joint from the body, generated effective and safe treatments. Our recent studies in the mouse tibia fracture model of complex regional pain syndrome (CRPS) demonstrated that all CRPS patients expressed IgM autoantibodies with pronociceptive passive transfer effects after intraplantar injection into the injured hindlimb or intrathecal injection into muMT fracture mice lacking B cells and immunoglobulin, and these pronociceptive CRPS IgM effects were mediated by C5a complement signaling and inflammatory cytokine release. Tibia fracture in mice caused an increase of C5a receptor (C5aR) expressing macrophages in the fracture limb dermis and C5aR expressing microglia in the corresponding spinal cord segments, and these activated immune cells release pronociceptive inflammatory cytokines in response to C5a signaling. Moreover, after fracture in mice, exaggerated neuropeptide and sympathetic adrenergic signaling stimulated pronociceptive IgM antibody accumulation in the skin and spinal cord. These observations are potentially paradigm shifting. The central hypothesis guiding our work is that tissue trauma causes neural activation of the innate and adaptive systems of immunity, with localized neoantigen expression in the injured tissue and corresponding spinal cord triggering lymph organ germinal center reactions characterized by the formation germinal B cells, with subsequent pronociceptive immune complex deposition and complement activation supporting localized chronic nociceptive sensitization. The primary objective of this proposal is to identify specific pharmacologic targets for the successful treatment of LBP and OA. The specific aims are; 1) to identify the autoimmune responses mediating nociceptive sensitization in the lumbar disc puncture (DP) mouse model of chronic LBP and in the monosodium iodoacetate arthritis (MIA) mouse model of chronic OA knee pain, to determine the prevalence of pronociceptive antibodies in LBP and OA patients, and to identify adaptive immune responses in LBP patient spinal discs and OA patient joints, 2) to temporally map the formation of lymph node germinal centers, characterized by the induction of T follicular helper cells (Tfh), germinal center B cells, and the production of pronociceptive antibodies in the DP and MIA mouse models, and 3) to determine whether sensory neuropeptide and sympathetic adrenergic signaling constitute a unifying mechanism for the activation and maintenance of the immune response to tissue injury. These experiments potentially will establish a rigorous foundation for exploring mechanisms of tissue injury induced autoimmunity, advance our understanding of musculoskeletal pain, and identify specific targets for future clinical trials.


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 = $511,139 )
2025	2025	PALO ALTO VETERANS INSTITUTE FOR RESEARCH	3801 MIRANDA AVE	PALO ALTO	CA	94304	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	8/15/2025	NON-COMPETING CONTINUATION	$511,139
														Subtotal = $511,139

Issue Date FY: 2024 ( Subtotal = $529,696 )
2024	2024	PALO ALTO VETERANS INSTITUTE FOR RESEARCH	3801 MIRANDA AVE	PALO ALTO	CA	94304	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	8	7/25/2024	NON-COMPETING CONTINUATION	$529,696
2024	2022	PALO ALTO VETERANS INSTITUTE FOR RESEARCH	3801 MIRANDA AVE	PALO ALTO	CA	94304	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	10/25/2023	COMPETING CONTINUATION	$19
2024	2020	PALO ALTO VETERANS INSTITUTE FOR RESEARCH	3801 MIRANDA AVE	PALO ALTO	CA	94304	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	10/25/2023	NON-COMPETING CONTINUATION	-$19
														Subtotal = $529,696

Issue Date FY: 2023 ( Subtotal = $542,135 )
2023	2023	PALO ALTO VETERANS INSTITUTE FOR RESEARCH	3801 MIRANDA AVE	PALO ALTO	CA	94304	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	8/1/2023	NON-COMPETING CONTINUATION	$542,135
														Subtotal = $542,135

Issue Date FY: 2022 ( Subtotal = $528,207 )
2022	2022	PALO ALTO VETERANS INSTITUTE FOR RESEARCH	3801 MIRANDA AVE BLDG 101 A2-210	PALO ALTO	CA	94304	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	9/6/2022	COMPETING CONTINUATION	$528,207
														Subtotal = $528,207

Issue Date FY: 2020 ( Subtotal = $335,881 )
2020	2020	PALO ALTO VETERANS INSTITUTE FOR RESEARCH	3801 MIRANDA AVE BLDG 101 A2-210	PALO ALTO	CA	94304	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	8/19/2020	NON-COMPETING CONTINUATION	$335,881
														Subtotal = $335,881

Issue Date FY: 2019 ( Subtotal = $334,753 )
2019	2019	PALO ALTO VETERANS INSTITUTE FOR RESEARCH	3801 MIRANDA AVE BLDG 101 A2-210	PALO ALTO	CA	94304	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	8/22/2019	NON-COMPETING CONTINUATION	$334,753
														Subtotal = $334,753

Issue Date FY: 2018 ( Subtotal = $352,335 )
2018	2018	PALO ALTO VETERANS INSTITUTE FOR RESEARCH	3801 MIRANDA AVE BLDG 101 A2-210	PALO ALTO	CA	94304	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	8/16/2018	NON-COMPETING CONTINUATION	$352,335
														Subtotal = $352,335

Issue Date FY: 2017 ( Subtotal = $352,335 )
2017	2017	PALO ALTO VETERANS INSTITUTE FOR RESEARCH	3801 MIRANDA AVE BLDG 101 A2-210	PALO ALTO	CA	94304	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	8/24/2017	NON-COMPETING CONTINUATION	$352,335
														Subtotal = $352,335

Issue Date FY: 2016 ( Subtotal = $352,335 )
2016	2016	PALO ALTO INSTITUTE FOR RESEARCH & EDUCATION, INC	P.O. BOX V 38	PALO ALTO	CA	94304	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	6/22/2016	NEW	-$7,249
2016	2016	PALO ALTO INSTITUTE FOR RESEARCH & EDUCATION, INC	P.O. BOX V 38	PALO ALTO	CA	94304	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	6/17/2016	NEW	$359,584
2016	2016	PALO ALTO VETERANS INSTITUTE FOR RESEARCH	POST OFFICE BOX V38	PALO ALTO	CA	94304	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	1	6/24/2016	NEW	$0
														Subtotal = $352,335

Grand Total All Awards = $3,838,816

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Neural immunoregulation of post-traumatic autoimmunity

Award Number: R01NS094438

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: 09/01/2016

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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