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Dysregulation of inflammation resolution as therapeutic target for IBD

Award Number: K01DK133666
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 07/01/2023
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Dysregulation of inflammation resolution as therapeutic target for IBD - ABSTRACT Promoting inflammation resolution and resolution-dependent intestinal epithelial wound healing are recent therapeutic concepts for IBD. During inflammation resolution, macrophages phagocytose apoptotic neutrophils (efferocytosis), thereby preventing secondary necrosis. Macrophage efferocytosis also stimulates the secretion of various resolving and reparative factors that can trigger intestinal epithelial wound healing. I previously reported that dysregulation of macrophage efferocytosis and efferocytosis-dependent intestinal epithelial wound healing contributed to pathogenesis in a murine model of Crohn’s disease (CD). The overall goal of this project is to build upon my prior work to advance human pre-clinical research into resolution-based therapies for CD. First, I seek to leverage innovative human models and unbiased analytical techniques to determine the cell-cell communication between efferocytic macrophages and human small intestinal epithelium that drives epithelial wound healing following inflammatory injury. This work will fill important knowledge gaps, identify potential resolution-specific therapeutic targets, and define a physiological baseline against which to assess disease- dependent dysregulation of this resolution/repair module. Towards this first goal, I have recently modeled inflammatory injury in human ileal and jejunal intestinal epithelial organoid culture systems and shown that human macrophage efferocytosis rescues this injury. I will interrogate this model with multi-omic techniques in order to reconstruct potential ligand-receptor interactions and receptor-signaling pathways. Second, I seek to investigate and translationally target potential disease-dependent dysregulations of macrophage efferocytosis and efferocytosis-dependent human small intestinal epithelial wound healing. I have observed, consistent with prior reports, that mucosal oxidized polyunsaturated fatty acids including 12- and 15- hydroxyeicosatetraenoic acid (HETE) correlate with disease in murine models of IBD and in IBD patient biopsies. In my human models, these HETEs act as potential dysregulators of resolution—suppressing both macrophage efferocytosis and efferocytosis-dependent small intestinal epithelial wound healing. I will investigate the mechanisms of these dysregulations. Nonetheless, I had previously observed that the apolipoprotein A1 mimetic peptide 4F rescues murine CD-like disease by enhancing mucosal excretion of disease-elevated HETEs. Pilot data show that 4F inhibits HETE-dependent human macrophage dysregulation and enhances the clearance of HETEs across human small intestinal primary epithelium. 4F thus appears to be a promising therapy against HETE-dependent dysregulation of resolution and resolution-repair. After this study, I anticipate that I will have characterized novel dysregulations of inflammation resolution and resolution-dependent intestinal epithelial repair that may amplify disease in IBD but that can nonetheless be disrupted therapeutically by exploiting a novel mucosal clearance pathway.


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 = $161,566 )
2025	2025	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	3/28/2025	NON-COMPETING CONTINUATION	$161,566
														Subtotal = $161,566

Issue Date FY: 2024 ( Subtotal = $161,566 )
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	3/29/2024	NON-COMPETING CONTINUATION	$161,566
														Subtotal = $161,566

Issue Date FY: 2023 ( Subtotal = $163,122 )
2023	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	5/26/2023	NEW	$163,122
														Subtotal = $163,122

Grand Total All Awards = $486,254

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Dysregulation of inflammation resolution as therapeutic target for IBD

Award Number: K01DK133666

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 07/01/2023

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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