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Elucidating Fh15-Mediated Modulation of TLR4/NF-kB in Neutrophils to SuppressInflammation in Sepsis and Ulcerative colitis

Award Number: R16AI203189
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: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2030

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Elucidating Fh15-Mediated Modulation of TLR4/NF-kB in Neutrophils to SuppressInflammation in Sepsis and Ulcerative colitis - The increasing application of helminth antigen-derived therapy to prevent inflammatory diseases represents a promising and innovative approach. Over the past decade, our research group has concentrated on Fh15, a recombinant molecule from the Fasciola hepatica fatty acid binding protein family, which exhibits potent antiinflammatory effects in animal models of sepsis and ulcerative colitis. We have demonstrated that a single intraperitoneal (i.p.) dose of Fh15 administered to animals one hour before or after the administration of a lethal dose of lipopolysaccharide (LPS) or live E. coli infusion significantly suppresses the cytokine storm and other inflammatory markers. Additionally, we found that a single i.p. dose of Fh15 given three times, two days apart, significantly improves the disease activity index (DAI) in a dextran sulfate sodium (DSS)-induced ulcerative colitis mouse model. These therapeutic effects correlated with reduced levels of intestinal inflammatory markers, diminished neutrophil infiltration, and lower levels of myeloperoxidase—a protein essential for neutrophil extracellular trap (NET) formation. Furthermore, we demonstrated that Fh15 can inhibit NETosis in human neutrophils and acts as a TLR4 antagonist, a receptor involved in the immune response against sepsis and ulcerative colitis, as well as in neutrophil activation and NET release. This application stems from a previous SC1 grant (1SC1AI155439-01), which resulted in one patent, approximately five publications, and the graduation of three PhD and one MS students. Our central hypothesis posits that Fh15 modulates the TLR4/NF-êB signaling pathway to suppress inflammation in animal models of sepsis and ulcerative colitis, which is associated with decreased concentrations of free extracellular DNA (eDNA) and reduced NETosis. In the aim-1 will demonstrate the relationship between the suppression of inflammatory markers induced by Fh15 in the sepsis and ulcerative colitis models and the reduction of eDNA and NETs in vivo. We will isolate free eDNA from plasma in sepsis and colitis mice treated with Fh15 and characterize the specific protein-DNA components of this eDNA through immunofluorescence staining and confocal microscopy. The results will be correlated with levels of inflammatory markers for colitis and sepsis. In the aim-2 will identify the mechanisms underlying the inhibitory effects of Fh15 on NETosis. We will isolate neutrophils from mouse bone marrow and analyze activation markers such as CD11b, CD66b, CD62L, CD64, and FcRI using flow cytometry. Additionally, we will assess the expression of TLR4, CD14, and proteins involved in the NF-êB pathway using qPCR and Western blotting. Proximity ligation assays will determine whether Fh15 directly interacts with CD14 on these cells. We will also employ proteomics and single-cell RNA sequencing to investigate changes in protein and gene expression in neutrophils and identify molecules involved in pro-inflammatory pathways that may be regulated by Fh15. The outcome of this study will provide a more comprehensive understanding of how F. hepatica molecules interact with the immune system and lay the groundwork for the development of a novel class of anti-inflammatory drugs.


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 = $149,000 )
2026	2026	UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS	B622 MAIN BUILDING FLR 6	SAN JUAN	PR	00935	SAN JUAN	USA	Allergy and Infectious Diseases Research	000	1	9/1/2026	NEW	$149,000
														Subtotal = $149,000

Grand Total All Awards = $149,000

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Elucidating Fh15-Mediated Modulation of TLR4/NF-kB in Neutrophils to SuppressInflammation in Sepsis and Ulcerative colitis

Award Number: R16AI203189

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: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2030

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