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Notch regulation of airway epithelial-immune cell cross-talk in SARS-CoV-2 infection

Award Number: R21AI194204
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: 07/09/2025
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Notch regulation of airway epithelial-immune cell cross-talk in SARS-CoV-2 infection - Abstract Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the causative agent of COVID-19. Infection with SARS-CoV-2 begins in epithelial cells of the upper airways, which triggers multiple antiviral responses that activate myeloid immune cells, coordinate the early innate immune response, and limit viral spread. Notably, our understanding of the cell signaling mechanisms that regulate early epithelial-immune cell interactions and induction of tissue pathology during SARS-CoV-2 infection of the human airway remains limited. To investigate these processes, we have developed a novel in vitro all human 3D model of the upper airways (HUA) composed of layers of primary differentiated airway epithelial cells expressing ACE2, lung fibroblasts in a collagen matrix, and pulmonary endothelial cells, with myeloid cells present in each layer. SARS-CoV-2 infection of the HUA model results in virus replication and induction of an immune response reminiscent of in vivo infection, and the presence of myeloid cells limits viral replication. Therefore, we will use the HUA model to perform kinetic studies of the mechanisms by which human airway cells interact to regulate virus-host interactions, inflammation, and tissue pathology associated with SARS-CoV-2. We will focus on the Notch pathway, which acts via direct cell- to-cell signaling to regulate airway epithelial cell fate decisions as well as myeloid cell maintenance, Toll-like receptor signaling, pro-inflammatory polarization, and antiviral functions. However, the mechanisms by which Notch signaling regulates airway epithelial-myeloid cell interactions during SARS-CoV-2 infection remain unknown. Our preliminary analyses showed that airway epithelial cells and myeloid cells express multiple Notch ligands and receptors in uninfected HUA models, suggesting that the Notch pathway will mediate bidirectional crosstalk during the airway response to infection. We will test the central hypothesis that Notch receptor signaling in myeloid cells regulates their pro-inflammatory phenotype, thereby promoting the host innate antiviral immune response and contributing to airway epithelial cell damage and remodeling during SARS-CoV-2 infection. Using lentivirus vectors and inducible expression systems, we will attenuate expression of individual Notch ligands and receptors in a cell-type specific and temporal manner. Following SARS-CoV-2 infection, we will quantify the impact of reducing Notch signaling activity on virus replication, myeloid cell phenotypes, the host immune response, and airway epithelial remodeling. The data collected in this study will advance our understanding of the mechanisms that regulate airway epithelial-immune cell interactions during SARS-CoV-2 infection and may identify candidate therapeutic targets in the Notch pathway to enhance antiviral immunity and reduce epithelial injury and remodeling in the upper airway.


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 = $0 )
2026	2025	OKLAHOMA MEDICAL RESEARCH FOUNDATION	825 NE 13TH ST	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Allergy and Infectious Diseases Research	000	1	2/6/2026	NEW	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $448,688 )
2025	2025	OKLAHOMA MEDICAL RESEARCH FOUNDATION	825 NE 13TH ST	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Allergy and Infectious Diseases Research	000	1	7/9/2025	NEW	$448,688
														Subtotal = $448,688

Grand Total All Awards = $448,688

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Notch regulation of airway epithelial-immune cell cross-talk in SARS-CoV-2 infection

Award Number: R21AI194204

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: 07/09/2025

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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