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TRPV1-dependent neuro-immune modulation and regulation of endogenous acyl-dopamines in sepsis and acute inflammation

Award Number: R01AI168265
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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TRPV1-dependent neuro-immune modulation and regulation of endogenous acyl-dopamines in sepsis and acute inflammation - PROJECT SUMMARY Sepsis is a formidable public health problem, and there is a need to better understand the basic mechanisms of sepsis and immunomodulation. Our studies will define the anti-inflammatory mechanisms and functional effects in sepsis of N-oleoyl dopamine (OLDA) and N-arachidonoyl dopamine (NADA), which are endogenous acyl-dopamines produced in the peripheral and central nervous systems (PNS, CNS). OLDA and NADA exhibit activity at the transient receptor potential vanilloid 1 (TRPV1) and cannabinoid receptor 1 (CB1R). In mice with S. aureus pneumonia, intraabdominal polymicrobial sepsis, or endotoxemia, we found that OLDA or NADA administration 1) induces an early substantial upregulation of systemic IL-10, 2) decreases pro-inflammatory cytokines and chemokines, and 3) reduces acute lung injury and sepsis scores at 24 hours. NADA also reduces CGRP and increases Substance P in the plasmas of LPS-treated mice. Our studies in bone marrow chimeras of Trpv1-/- and wild-type mice indicated that NADA induces IL-10 via TRPV1 expressed by non- myeloid cells. Our further preliminary data suggest that neuronal TRPV1 mediates the anti-inflammatory and protective actions of OLDA in LPS-treated mice, and more specifically, that these effects are mediated by TRPV1 neurons in the CNS rather than the PNS. Finally, we observed increased plasma and brain levels of OLDA and NADA in LPS-treated mice, which suggest that these novel endogenous lipids may be dynamically regulated during acute inflammation and sepsis. Collectively, our data have led to our central hypothesis that there is a CNS based neuro-immunomodulatory link that involves the activation of neuronal TRPV1 by endogenous lipids, such as OLDA and NADA, and regulates inflammatory responses and outcomes of acute inflammation and sepsis. Aim #1 will localize the TRPV1 neurons responsible for the anti-inflammatory actions of OLDA and NADA in acute inflammation and sepsis and determine the role of CB1R in the TRPV1-dependent anti-inflammatory actions of OLDA and NADA. Aim #2 will identify the downstream mechanisms by which the activation of neuronal TRPV1 by OLDA or NADA upregulates IL-10 production by circulating monocytes in sepsis, focusing on the roles of Substance P, CGRP, and the sympathetic nervous system. Aim #3 will define the effects of OLDA and NADA on sepsis outcomes, and the effects of sepsis on endogenous production of OLDA and NADA, and expression of TRPV1 and CB1R. These studies will advance the understanding of the neuro-immunomodulatory effects and endogenous roles of NADA, OLDA and TRPV1 in sepsis, with the ultimate goal to identify novel therapeutic targets.


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 = $1,002,830 )
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	001	4	6/5/2025	EXTENSION WITH OR WITHOUT FUNDS	$1,002,830
2025	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	3	6/5/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,002,830

Issue Date FY: 2024 ( Subtotal = $509,449 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	3	5/21/2024	NON-COMPETING CONTINUATION	$509,449
														Subtotal = $509,449

Issue Date FY: 2023 ( Subtotal = $525,561 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	2	5/17/2023	NON-COMPETING CONTINUATION	$525,561
														Subtotal = $525,561

Issue Date FY: 2022 ( Subtotal = $541,674 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	1	6/3/2022	NEW	$541,674
														Subtotal = $541,674

Grand Total All Awards = $2,579,514

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TRPV1-dependent neuro-immune modulation and regulation of endogenous acyl-dopamines in sepsis and acute inflammation

Award Number: R01AI168265

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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