Thursday, November 21, 2024 11/21/2024

Paper-based cultures supporting tissue-like structures for biochemical studies of oxygen gradients and screening applications

Award Number: R35GM128697
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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MIRA Abstract This MIRA renewal builds upon the success of our efforts to develop a readily accessible culture platform to generate tissue-like structures and quantify cellular responses in physiologically relevant environments. Oxygen is a master regulator of cellular function, responsible for systematic reprogramming under hypoxic conditions and fine-tuning as oxygen supplies decrease. The tissue environment is spatially and temporally dynamic, responding to changes in oxygen and nutrient supplies as well as localized and systemic gradients of cell- generated signaling molecules. Despite the complexity of the tissue microenvironment, laboratories have relied on monolayer cultures due to standardized procedures for setup and analysis. We recognized the need for a culture platform to study cellular responses in defined tissue-like architectures whose extracellular microenvironment could be engineered and quantified. The paper-based culture platform represents a readily adoptable platform, which is modular in design and has a low technical barrier to entry. By stacking cell-laden sheets of paper, tissues are generated on demand. Our continued efforts include technological advances and the systematic study of oxygen's role in regulating (1) Estrogen signaling pathways in mammary tissue models. (2) The post-differentiation of drug-metabolizing enzymes of hepatocytes in a sinusoid model. We showed that hypoxia alters the regulation of estrogen receptor alpha (ERa) in ER+ breast lines, decreasing transactivation but maintaining similar amounts of protein in the presence and absence of estrogen. These results are markedly different from monolayers of the same cells in hypoxia. As we continue to develop the mammary tissue model, we will include stromal components to determine how they (alone and in concert with hypoxia) alter estrogen signaling. Our goal is to use a multi-pronged approach to generate a map of the "estrome," visualizing the transcriptional, translational, and activity changes of ERa and ERb to better predict in vivo outcomes. Our characterization of HepaRG cells under representative periportal and perivenous oxygen tensions shows its importance in the post-differentiation expression and activity of drug-metabolizing enzymes and transport proteins. We will continue to develop a sinusoid model that can characterize the HepaRG cells under a full range of oxygen tensions that span the sinusoid in vivo, incorporating non-parenchymal cells known to provide morphogens that promote this process and including flowing medium to simulate the constant exchange occurring in the sinusoid. The previous funding period's biological inquiries and technological developments enable these new directions. We will continue to incorporate commonly used analysis tools while developing ways to characterize the system further while not straying from the original goal of a modular platform that is both reproducible and quickly adopted. Our biological inquiries will result in more predictable cell-based platforms, allowing for the: discovery of new biomarkers and treatments, the ability to confidently assess new drugs for hepatotoxicity and potential drug-drug interactions, and a better understanding of disease progression.


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	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	000	6	11/6/2024	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $368,474 )
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	000	6	8/8/2024	COMPETING CONTINUATION	$368,474
														Subtotal = $368,474

Issue Date FY: 2022 ( Subtotal = $365,351 )
2022	2022	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	000	5	7/20/2022	NON-COMPETING CONTINUATION	$365,351
														Subtotal = $365,351

Issue Date FY: 2021 ( Subtotal = $365,351 )
2021	2021	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	000	4	7/1/2021	NON-COMPETING CONTINUATION	$365,351
														Subtotal = $365,351

Issue Date FY: 2020 ( Subtotal = $442,776 )
2020	2020	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	001	3	6/15/2020	NON-COMPETING CONTINUATION	$365,351
2020	2020	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	000	2	6/9/2020	SUPPLEMENT FOR EXPANSION	$77,425
														Subtotal = $442,776

Issue Date FY: 2019 ( Subtotal = $483,599 )
2019	2019	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	001	2	6/19/2019	SUPPLEMENT FOR EXPANSION	$118,248
2019	2019	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	000	2	6/14/2019	NON-COMPETING CONTINUATION	$365,351
														Subtotal = $483,599

Issue Date FY: 2018 ( Subtotal = $365,351 )
2018	2018	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	000	1	7/2/2018	NEW	$365,351
														Subtotal = $365,351

Grand Total All Awards = $2,390,902

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Paper-based cultures supporting tissue-like structures for biochemical studies of oxygen gradients and screening applications

Award Number: R35GM128697

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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