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A physiological and translational liver model to study the metabolism-modulating roles of extracellular matrix microstructures

Award Number: R35GM146779
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/10/2022
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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A physiological and translational liver model to study the metabolism-modulating roles of extracellular matrix microstructures - ABSTRACT My laboratory has been dedicated to developing physiologically relevant yet easy-to-apply tissue modeling technologies, and exploring the interactions between extracellular matrix (ECM) microstructures and cell metabolisms. Building on recent successes and discoveries, we propose to develop a more advanced technology for liver modeling, and to profoundly study how fibrosis-relevant ECM microstructures can impair hepatic metabolism—the former aims to reduce the monetary/time costs and human subject risks in new drug development, and the latter will provide new understanding and metabolic targets for fibrosis treatments. Although various microfluidic liver models have been reported, they lack the critical compositions of the physiological liver, namely, all the necessary cell types, the relevant architecture, and physiological 3D ECMs. Both literature and our preliminary results suggest the crucial roles of these components in maintaining hepatic functions and homeostasis, which may explain why current liver models could only mimic part of the functions. Integrating the various cell types, the cellular architecture, and the 3D ECMs represents challenging hurdles by the available technologies. Therefore, we propose an innovative technology to model the liver with a new fabrication logic, workflow, and set of technical means. This technology will recapitulate the most liver niche properties heretofore, but with relatively simple and straightforward operations (setting up, maintenance, analyses, etc.). We recently reported for the first time that ECM microstructures could modulate metabolic activities in various cell types. Based on this, we propose to set up ECM controls that mimic healthy and fibrotic conditions, and thoroughly investigate how the aberrantly remodeled ECMs can impair hepatic metabolisms. Mechanistic studies involving integrins and AMP-activated protein kinase are also planned. To summarize, there has not been a tissue modeling technology like the proposed one; and others have not reported the interactions between ECM microstructures and cell metabolism. The proposed work, therefore, represents high novelty and my laboratory’s unique space in the field. Completing the proposed studies will be significant for pharmaceutical developments because a new testing/screening platform and metabolic (metabolites and the controlling proteins) targets will be provided for future fibrosis therapies.


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 = $333,124 )
2025	2025	UNIVERSITY OF MARYLAND BALTIMORE COUNTY	1000 HILLTOP CIR	BALTIMORE	MD	21250	BALTIMORE	USA	Biomedical Research and Research Training	000	4	7/15/2025	NON-COMPETING CONTINUATION	$333,124
														Subtotal = $333,124

Issue Date FY: 2024 ( Subtotal = $333,618 )
2024	2024	UNIVERSITY OF MARYLAND BALTIMORE COUNTY	1000 HILLTOP CIR	BALTIMORE	MD	21250	BALTIMORE	USA	Biomedical Research and Research Training	000	3	8/1/2024	NON-COMPETING CONTINUATION	$333,618
														Subtotal = $333,618

Issue Date FY: 2023 ( Subtotal = $334,089 )
2023	2023	UNIVERSITY OF MARYLAND BALTIMORE COUNTY	1000 HILLTOP CIR	BALTIMORE	MD	21250	BALTIMORE	USA	Biomedical Research and Research Training	000	2	7/24/2023	NON-COMPETING CONTINUATION	$334,089
														Subtotal = $334,089

Issue Date FY: 2022 ( Subtotal = $333,128 )
2022	2022	UNIVERSITY OF MARYLAND BALTIMORE COUNTY	1000 HILLTOP CIR	BALTIMORE	MD	21250	BALTIMORE	USA	Biomedical Research and Research Training	000	1	8/3/2022	NEW	$333,128
														Subtotal = $333,128

Grand Total All Awards = $1,333,959

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A physiological and translational liver model to study the metabolism-modulating roles of extracellular matrix microstructures

Award Number: R35GM146779

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/10/2022

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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