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AMPK in the Development and resolution of Lung Fibrosis

Award Number: R01HL139617
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/15/2019
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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AMPK in the Development and resolution of Lung Fibrosis - PROJECT SUMMARY Clearance of apoptotic cells (efferocytosis) is significantly reduced in lungs of patients with the fibrosing lung disorder, idiopathic pulmonary fibrosis (IPF). Mechanism/s responsible for halted efferocytosis and the potential benefit of restoring efferocytosis to fibrosis resolution has yet to be determined. The major goal of the proposed studies is to establish how AMP-activated protein kinase (AMPK) affects macrophage population dynamics, including influx of monocyte-derived transitional macrophages that promote fibrosis persistence versus efferocytosis-competent populations involved in resolution of fibrosis. Macrophage dynamics and secretome will be investigated in young-adult mice with resolving fibrosis, as well as the effect of AMPK-dependent stimulation of efferocytosis and induced fibrosis resolution in aged mice. For specific role of AMPK in lung macrophages, we will use AMPK deficient mice and adoptive transfer studies of macrophages in aged mice. The central hypothesis is that: Senomorphic effects of AMPK promotes efferocytosis and resolution of age-associated persistent lung fibrosis. Our Specific AIMs are designed to determine how AMPK activation affects macrophage phenotypes for clearance of apoptotic cells during established lung fibrosis versus resolution (AIM 1). AIM2 will establish the impact of AMPK activation in distinct areas of fibrotic vs. resolution niche, using spatial transcriptomics, with focus on AMPK-dependent regulation of mitochondrial and lysosomal biogenesis to restore efferocytotic competence in lung macrophages. AIM3 will delineate how AMPK activation reverses the non- autonomous mechanism of efferocytosis suppression. Our findings will characterize efferocytosis-competent macrophages in the fibrosis resolution niche, as well as the impact of AMPK on pro-fibrogenic population of MФs (CX3CR1+SiglecF+). Furthermore, our findings is expected to motivate clinical studies of metformin or newer classes of direct allosteric activators (e.g., MK-8722) of AMPK to test the gero-protective role of AMPK in chronic fibrotic disorders such as IPF.


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 ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	001	5	4/3/2025	COMPETING CONTINUATION	$114,786
2025	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	000	4	4/3/2025	NON-COMPETING CONTINUATION	-$114,786
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $761,371 )
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	004	5	8/12/2024	COMPETING CONTINUATION	$761,371
2024	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	002	4	4/18/2024	NON-COMPETING CONTINUATION	$0
2024	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	001	4	4/16/2024	NON-COMPETING CONTINUATION	$217,680
2024	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	003	4	8/1/2024	NON-COMPETING CONTINUATION	$0
2024	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	000	4	3/28/2024	NON-COMPETING CONTINUATION	-$217,680
														Subtotal = $761,371

Issue Date FY: 2022 ( Subtotal = $528,465 )
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	000	4	12/28/2021	NON-COMPETING CONTINUATION	$475,618
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	001	4	6/13/2022	NON-COMPETING CONTINUATION	$52,847
														Subtotal = $528,465

Issue Date FY: 2021 ( Subtotal = $528,465 )
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	001	3	5/19/2021	NON-COMPETING CONTINUATION	$52,847
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	000	3	12/21/2020	NON-COMPETING CONTINUATION	$475,618
														Subtotal = $528,465

Issue Date FY: 2020 ( Subtotal = $528,465 )
2020	2020	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	001	2	1/31/2020	NON-COMPETING CONTINUATION	$26,424
2020	2020	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	000	2	1/8/2020	NON-COMPETING CONTINUATION	$502,041
														Subtotal = $528,465

Issue Date FY: 2019 ( Subtotal = $528,465 )
2019	2019	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	000	1	1/15/2019	NEW	$528,465
														Subtotal = $528,465

Grand Total All Awards = $2,875,231

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AMPK in the Development and resolution of Lung Fibrosis

Award Number: R01HL139617

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/15/2019

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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