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Antimicrobial mechanisms of Specialized Proresolving Medicators

Award Number: R01AI128202
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2018
PERIOD OF PERFORMANCE END DATE: 05/31/2024

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Antimicrobial mechanisms of Specialized Proresolving Medicators - Project summary Despite advances in antibiotic therapy, there is a significant need for more efficacious treatments of severe bacterial infections. The host responds to bacterial infection by activating the innate immune system to clear pathogen by phagocytic and killing mechanisms, resolve inflammation and return to homeostasis. In sepsis, activation of host response causes massive inflammation as well as a later paradoxical dysregulated inflammatory response where the host is immunocompromised and is susceptible to secondary infections. Specialized Pro-resolving Mediators (SPMs) are endogenously produced lipid mediators with infection resolution activity. A recent report showed that there was a temporal difference in release of different SPMs where early increase of Resolvins (Rvs) was associated with infection resolution. We and others show that SPMs, such as Lipoxin A4 (LXA4), and Rvs increased survival, decreased systemic inflammatory response and reduced bacteria load in cecal ligation and puncture (CLP) sepsis or other models of bacterial infection. We obtained evidence that LXA4 increased Fcγ receptor1 (FcγR1) dependent neutrophil phagocytic ability in CLP- sepsis while Rvs D1 and D2 increased human monocyte phagocytosis of Pseudomonas aeruginosa (P. aeruginosa) suggesting that SPMs can promote host defense to clear pathogen in sepsis. Quorum sensing is a cell density dependent mechanism which regulates expression and release of bacterial virulence factors. We have evidence that LXA4 inhibits binding of the bacterial quorum sensor 3-oxo- C12 HSL in P. aeruginosa with a potency approximately 1000-fold greater than known quorum sensing inhibitors. LXA4 reduced release of the exotoxin - pyocyanin which suggests that LXA4 may reduce bacterial virulence by quorum sensing inhibition. This is the first evidence that an endogenously produced compound can both augment host defense and directly reduce bacterial virulence. Therefore, we hypothesize that SPMs promote infection resolution by enhancing host defense and reducing bacterial virulence. 3 Specific Aims are proposed. In AIM 1 we will test the hypothesis that SPMs enhance host defense to resolve infection in the 2-hit model of CLP sepsis with secondary Pseudomonas lung infection. In AIM 2 we will test the hypothesis that the cellular mechanism of SPM enhanced antimicrobial leukocyte function is by promoting activity Rho GTPases and differentiation of monocytes to a pro-resolution phenotype. In AIM 3 we will determine if SPMs inhibit quorum sensing and reduce bacterial virulence. We believe investigation of SPM mediated mechanisms of antimicrobial activity may have broad applications in bacterial infections and may contribute to new treatments.


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 = $0 )
2025	2022	RU SCHOOL OF OSTEOPATHIC MEDICINE	42 E LAUREL RD	STRATFORD	NJ	08084	CAMDEN	USA	Allergy and Infectious Diseases Research	000	5	1/9/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $402,500 )
2022	2022	RU SCHOOL OF OSTEOPATHIC MEDICINE	42 E LAUREL RD	STRATFORD	NJ	08084	CAMDEN	USA	Allergy and Infectious Diseases Research	000	5	5/16/2022	NON-COMPETING CONTINUATION	$402,500
														Subtotal = $402,500

Issue Date FY: 2021 ( Subtotal = $402,500 )
2021	2021	RU SCHOOL OF OSTEOPATHIC MEDICINE	42 E LAUREL RD	STRATFORD	NJ	08084	CAMDEN	USA	Allergy and Infectious Diseases Research	000	4	5/13/2021	NON-COMPETING CONTINUATION	$402,500
														Subtotal = $402,500

Issue Date FY: 2020 ( Subtotal = $402,500 )
2020	2020	RU SCHOOL OF OSTEOPATHIC MEDICINE	42 E LAUREL RD	STRATFORD	NJ	08084	CAMDEN	USA	Allergy and Infectious Diseases Research	000	3	5/8/2020	NON-COMPETING CONTINUATION	$402,500
														Subtotal = $402,500

Issue Date FY: 2019 ( Subtotal = $402,500 )
2019	2019	RU SCHOOL OF OSTEOPATHIC MEDICINE	42 E LAUREL RD	STRATFORD	NJ	08084	CAMDEN	USA	Allergy and Infectious Diseases Research	000	2	5/21/2019	NON-COMPETING CONTINUATION	$402,500
														Subtotal = $402,500

Issue Date FY: 2018 ( Subtotal = $402,500 )
2018	2018	RU SCHOOL OF OSTEOPATHIC MEDICINE	42 E LAUREL RD	STRATFORD	NJ	08084	CAMDEN	USA	Allergy and Infectious Diseases Research	000	1	5/22/2018	NEW	$402,500
														Subtotal = $402,500

Grand Total All Awards = $2,012,500

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Antimicrobial mechanisms of Specialized Proresolving Medicators

Award Number: R01AI128202

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2018

PERIOD OF PERFORMANCE END DATE: 05/31/2024

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