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Scientific innovation for personalized severe asthma management

Award Number: P01HL158507
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2021
PERIOD OF PERFORMANCE END DATE: 04/30/2026

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Scientific innovation for personalized severe asthma management - PROJECT SUMMARY/ABSTRACT Our overall goal is to characterize the cell biology and physiology of recently identified mechanisms underlying severe asthma. Severe asthma is a disabling obstructive lung disease that accounts for the majority of the morbidity and mortality associated with asthma; it accounts for annual healthcare costs in excess of $10 billion in the United States alone. Severe asthma has been a particular focus of our therapeutic development efforts. We have discovered and studied three novel mechanisms relevant to severe asthma. These include the role in severe asthma of: 1) β2 adrenergic receptor regulation by S-nitrosylation; 2) airway acidification; and 3) androgen signaling. Each of these three mechanisms has the potential to be treated with novel, personalized therapies that will be studied in a complementary fashion in the third Aim of each Project. Three synergistic proposed Projects are proposed: Project 1, S-nitrosylation signaling in severe asthma; Project 2, airway pH regulation in severe asthma; and Project 3, androgen signaling in severe asthma. Note that a substantial amount of the science, and most of the proposed Cores, are currently incorporated in an NHLBI –sponsored Translational P01 at our two institutions, Indiana University and Case Western Reserve University. However, the NHLBI is not planning to renew its Translational P01 initiative. What this means for the current proposal, however, is that the scientific interface, as well as the Cores, are currently operational; and they are not duplicated at either institution. We propose to continue these Core functions in the current proposal. The three Projects have scientific synergy. For example, detrimental denitrosylation (Project 1) is reversed both by airway alkalinization (Project 2) and by airway epithelial androgen treatment (Project 3). Interleukin 17, which decreases airway epithelial S- nitrosothiol signaling (Project 1) is inhibited by airway alkalinization (Project 2) and androgen receptor signaling (Project 3). Interleukin 4 gene expression appears to be inhibited both by human airway alkalinization (Project 2) and by androgen receptor signaling (Project 3). These and related interactions will be studied in detail. The Program also has robust operational synergy. Each Project will make use of each core. In particular, each will use data and specimens from the Research Bronchoscopy and Biospecimens Core and from the Severe Asthma Clinical Trials Core; each will use cells from the Primary Human Airway Cell Culture Core; each will rely heavily on the Pulmonary Biostatistics Core for data analysis; and all projects and cores will be coordinated by an Administrative Core. Note that the Administrative Core will also assist all Projects with data dissemination, with speakers and with advisory boards. None of the three Projects would be able to support these Core functionalities as an independent R01. At the conclusion of this Program, we anticipate having used our basic science innovations to develop at least three novel approaches to managing severe asthma.


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 = $2,408,164 )
2025	2025	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Lung Diseases Research	000	5	6/27/2025	NON-COMPETING CONTINUATION	$2,408,164
														Subtotal = $2,408,164

Issue Date FY: 2024 ( Subtotal = $2,357,534 )
2024	2024	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Lung Diseases Research	000	4	5/8/2024	NON-COMPETING CONTINUATION	$2,357,534
														Subtotal = $2,357,534

Issue Date FY: 2023 ( Subtotal = $2,405,551 )
2023	2023	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Lung Diseases Research	000	3	6/10/2023	NON-COMPETING CONTINUATION	$2,405,551
														Subtotal = $2,405,551

Issue Date FY: 2022 ( Subtotal = $2,409,373 )
2022	2022	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Lung Diseases Research	000	2	7/8/2022	NON-COMPETING CONTINUATION	$2,409,373
														Subtotal = $2,409,373

Issue Date FY: 2021 ( Subtotal = $2,420,712 )
2021	2021	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Lung Diseases Research	000	1	7/28/2021	NEW	$2,420,712
														Subtotal = $2,420,712

Grand Total All Awards = $12,001,334

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Scientific innovation for personalized severe asthma management

Award Number: P01HL158507

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2021

PERIOD OF PERFORMANCE END DATE: 04/30/2026

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