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Postprandial activation of hyaluronan-MARCO axis contributes to systemic chronic inflammation

Award Number: R01DK136532
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Postprandial activation of hyaluronan-MARCO axis contributes to systemic chronic inflammation - PROJECT SUMMARY/ABSTRACT Systemic chronic inflammation (SCI) is a common comorbidity of type 2 diabetes (T2D) and inflammatory bowel disease (IBD), e.g., it affects 25-40% of IBD patients, contributing to extraintestinal manifestations of IBD. The contribution of postprandial inflammation to the SCI in those contexts remains unclear. Our preliminary data in T2D patients suggest hyaluronan (HA) correlates with plasma inflammatory cytokines, and postprandial HA is much higher in T2D patients, which can be quickly normalized by bariatric surgery. We modeled this postprandial HA spike in diet-induced obese animal models, and we found this phenomenon was more pronounced in IBD mouse models. With a new Has2 overexpression mouse model we generated in a recent publication studying adipose tissue HA, we found circulating HA can induce hepatic macrophage receptor with collagenous structure (Marco) expression. MARCO belongs to class A scavenger receptors. MARCO itself is not capable of eliciting inflammation, but may function with intracellular pattern recognition receptors to stimulate an inflammatory response. With new mouse models to either delete Marco or overexpress Marco, we showed it augmented postprandial inflammatory response, and required nucleotide-binding oligomerization domain containing 1 (NOD1) in this process. Based on these data, we hypothesize that meal induces quick displacement of HA from the intestinal tract, entering the circulation to induce Marco expression on liver macrophage – Kupffer cells (KCs). Saturated fatty acids from the diet use MARCO to be delivered into the cell to activate NOD1 to elicit an inflammatory response. With several genetically engineered mouse models, we will examine (A). the mechanism by which HA promotes Marco expression in KCs; (B) the role of liver macrophage Marco in cytokine secretion; (C) the source of inflammatory stimuli and the direct effector of KCs inflammatory response in three specific aims. Aim 1 will determine the role of HA in postprandial hepatic KC Marco expression; Aim 2 will determine the molecular mechanism by which KC MARCO enhances postprandial inflammation and contributes to SCI; and Aim 3 will evaluate whether digesting HA or neutralizing MARCO alleviates SCI and related pathologies. Completing the proposed research will provide novel scientific knowledge on the HA-MARCO axis in postprandial inflammation and SCI. This knowledge will support the idea of controlling circulating HA and neutralizing MARCO to combat SCI and related diseases.


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 = $433,816 )
2025	2025	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	5/2/2025	NON-COMPETING CONTINUATION	$433,816
														Subtotal = $433,816

Issue Date FY: 2024 ( Subtotal = $416,464 )
2024	2024	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	5/3/2024	NON-COMPETING CONTINUATION	$416,464
														Subtotal = $416,464

Issue Date FY: 2023 ( Subtotal = $433,816 )
2023	2023	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	6/7/2023	NEW	$433,816
														Subtotal = $433,816

Grand Total All Awards = $1,284,096

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Postprandial activation of hyaluronan-MARCO axis contributes to systemic chronic inflammation

Award Number: R01DK136532

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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