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Defining mechanisms of CC16 on epithelial-driven host responses to pathogens

Award Number: R01HL142769
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2019
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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Defining mechanisms of CC16 on epithelial-driven host responses to pathogens - Asthma and COPD are the most commonly diagnosed chronic lung diseases in the United States. Studies have shown that asthma is the most important risk factor for COPD that develops through a course of low lung function from school age that tracks into adulthood. However, there is a fundamental gap in understanding the basic underlying mechanisms of this progression. In the first cycle of funding, we addressed this gap by focusing on the role of CC16 in mediating the immune response that yields protection against lung function decline. We published several key reports providing mechanistic and clinical evidence supporting the notion that persistent early life infections in the context of CC16 deficits may be a previously overlooked link in understanding progression of asthma into severe asthma with fixed airflow limitation. Additionally, we identified 2 novel ligands for CC16’s protective activity in different compartments, a4b1(VLA-4) in the circulation and a2b1 (VLA-2) in the respiratory tract. By engaging with VLA-4 in circulation on activated leukocytes, CC16 limits cellular migration into the airways and reduces airway hyperresponsiveness. By engaging with VLA-2 on epithelial cells, CC16 promotes antimicrobial and antiviral secretion thereby aiding in host defense against pathogens. In this renewal application, we will continue these translational studies and test the overall hypothesis that CC16 protects against Rhinovirus (RV) infection by promoting epithelial-driven antiviral host responses and that early life infections in the context of low CC16 leads to epigenetic changes resulting in enhanced airway remodeling. RV is the most common trigger of asthma exacerbations, especially in severe asthmatics and elicits acute exacerbations. Since CC16 is known to be lower in asthma patients, we will test the hypothesis that epithelial-driven antiviral host responses are decreased in asthma patient nasal epithelial cell samples via CC16- dependent mechanisms and that delivery of rCC16 and CC16-derived peptidomimetics offers a therapeutic benefit by enhancing antiviral host responses, thereby reducing RV infection, and limiting airway remodeling. This hypothesis will be tested by pursuing three specific aims: 1) Determine mechanisms by which CC16 promotes epithelial-driven host defense against respiratory pathogens, 2) Examine the impact of CC16 deficiency during early life viral infection on lung development and function in adult life and 3) Determine if circulating CC16 levels and asthma status impact nasal epithelial cell production of antimicrobials and antivirals and if exogenous CC16 can augment production in a VLA-2 dependent manner.


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 = $601,809 )
2025	2025	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Lung Diseases Research	001	7	8/1/2025	NON-COMPETING CONTINUATION	$601,809
2025	2023	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Lung Diseases Research	000	5	2/17/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $601,809

Issue Date FY: 2024 ( Subtotal = $606,414 )
2024	2024	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Lung Diseases Research	000	6	9/4/2024	COMPETING CONTINUATION	$606,414
														Subtotal = $606,414

Issue Date FY: 2023 ( Subtotal = $438,356 )
2023	2023	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Lung Diseases Research	001	5	8/28/2023	NON-COMPETING CONTINUATION	$438,356
2023	2022	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Lung Diseases Research	000	4	8/7/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $438,356

Issue Date FY: 2022 ( Subtotal = $445,265 )
2022	2022	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Lung Diseases Research	000	4	7/1/2022	NON-COMPETING CONTINUATION	$445,265
														Subtotal = $445,265

Issue Date FY: 2021 ( Subtotal = $516,062 )
2021	2021	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Lung Diseases Research	000	3	7/29/2021	NON-COMPETING CONTINUATION	$516,062
														Subtotal = $516,062

Issue Date FY: 2020 ( Subtotal = $502,989 )
2020	2020	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Lung Diseases Research	000	2	7/22/2020	NON-COMPETING CONTINUATION	$502,989
														Subtotal = $502,989

Issue Date FY: 2019 ( Subtotal = $516,438 )
2019	2019	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Lung Diseases Research	000	1	8/25/2019	NEW	$516,438
														Subtotal = $516,438

Grand Total All Awards = $3,627,333

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Defining mechanisms of CC16 on epithelial-driven host responses to pathogens

Award Number: R01HL142769

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2019

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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