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Dysregulated Immunometabolism and Premature Senescence in Corticosteroid-Refractory Severe Asthma

Award Number: R35HL166219
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2023
PERIOD OF PERFORMANCE END DATE: 01/31/2030

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Dysregulated Immunometabolism and Premature Senescence in Corticosteroid-Refractory Severe Asthma - Our laboratory has been engaged in elucidating mechanisms of asthma pathogenesis for over two decades. These efforts resulted in the discovery of GATA-3 as the key molecular regulator of development of Th2 cells that promote allergic airway disease. Since our initial discovery, GATA-3 was successfully targeted in allergen- induced mild asthma in humans. While Th2-driven mild asthma is well recognized and therapeutically manageable with inhaled corticosteroids (CS), 5-10% of asthma is clinically deemed severe and these patients poorly respond to CS, even when used in large doses. To address this issue of disease heterogeneity and identify the underlying mechanisms, we have studied the airway immune cells of severe asthma (SA) patients using various tools of immunology and molecular biology including a high dimensional multi-omics approach. Side-by-side we have used new mouse models of SA established in our laboratory to validate potential targets for therapeutic intervention in vivo. These studies have led to another original and unexpected finding of a high IFN-g response (Type 1/T1 response) in bronchoalveolar lavage (BAL) T cells in a subset of SA patients, a large fraction of these T cells having features of tissue resident memory T cells (TRMs). A T1high immune response is increasingly being appreciated in SA in both children and adults in independent studies challenging the belief that IFN-g is always protective in asthma since it cross-regulates a T2 immune response. We have also identified a deleterious feed forward positive loop induced by CS due to co-operation between STAT1, downstream of IFN-g, and the glucocorticoid receptor (GR) that would cause unremitting IFN-g production in the airways. The ramifications of unremitting IFN-g production can be profound and damaging given its potential to induce cellular senescence. Intimately associated with the T1high immune response is also cellular metabolism since mitochondrial dysfunction results in high levels of IFN-g production. Emerging literature provides strong evidence of mitochondrial dysfunction in immune cells resulting in senescence and inflammaging. While replicative senescence and inflammaging are typically associated with old age, the notion of stress-induced premature senescence (SIPS) causing premature aging and decline is being entertained in lung diseases including idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD). Since IFN-g can induce senescence in surrounding cells, the driver of SIPS may be inflammatory immune cells, especially T1high TRMs. The key goal of the proposed research program is to interrogate lung and peripheral blood immune cells and lipids in the BAL fluid of patients to identify mechanisms that induce a CS- refractory inflammatory phenotype in SA. We believe our studies would identify novel therapeutic targets to prevent SIPS in SA which may have relevance in other lung diseases. The long-term funding and flexibility of the R35 mechanism will help me to continue to train a new generation of scientists interested in studying immune dysfunction to develop novel therapies for recalcitrant chronic lung diseases that can induce SIPS.


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 = $666,208 )
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Lung Diseases Research	000	3	2/26/2025	NON-COMPETING CONTINUATION	$666,208
														Subtotal = $666,208

Issue Date FY: 2024 ( Subtotal = $725,426 )
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Lung Diseases Research	001	2	6/20/2024	NON-COMPETING CONTINUATION	$59,218
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Lung Diseases Research	000	2	1/29/2024	NON-COMPETING CONTINUATION	$666,208
														Subtotal = $725,426

Issue Date FY: 2023 ( Subtotal = $743,410 )
2023	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Lung Diseases Research	000	1	1/31/2023	NEW	$743,410
														Subtotal = $743,410

Grand Total All Awards = $2,135,044

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Dysregulated Immunometabolism and Premature Senescence in Corticosteroid-Refractory Severe Asthma

Award Number: R35HL166219

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2023

PERIOD OF PERFORMANCE END DATE: 01/31/2030

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