Wednesday, December 24, 2025 12/24/2025

Role of GM-CSF in Alveolar Macrophage Self-Renewal

Award Number: R01HL149743
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2021
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Role of GM-CSF in Alveolar Macrophage Self-Renewal - ABSTRACT Alveolar macrophages (AMs) are believed to be a self-renewing cell population without a requirement of replenishment from extra-pulmonary sources in healthy adult mice; however, the mechanism(s) involved and whether replenishment occurs by stimulating the proliferation of progenitors or mature AMs are not known. We reported that lung levels of granulocyte/macrophage-colony stimulating factor (GM-CSF) control long-term maintenance of macrophages trans- planted into the lungs (via a reciprocal feedback loop) as well as endogenous AMs. My preliminary data demonstrate that GM-CSF is a critical regulator of AM mitochondrial turnover, integrity and functions and is required for fatty acid oxidation- derived energy production, processes vital to cell proliferation. Prior studies in a leukemia cell line (TF-1) suggest the pleotropic effects of GM-CSF on macrophages may be mediated by biphasic, ligand concentration-dependent receptor signaling, i.e., low levels of GM-CSF promote survival and differentiation (but not proliferation) while high levels also stim- ulate proliferation. Our long-term goal is to determine mechanisms responsible for AM self-renewal. The objective here is to elucidate the mechanism by which GM-CSF regulation of mitochondrial homeostasis controls AM self-renewal. Cen- tral Hypothesis: AMs are maintained by homeostatic self-renewal driven by GM-CSF threshold-triggered/concentration- dependent, niche-limited proliferation of mature (long-lived) AMs (not progenitors). Rationale: This hypothesis was de- veloped based on my reported and preliminary data demonstrating GM-CSF deficiency results in reduced mitochondrial metabolism and integrity despite increased mitochondrial mass. Approach: I will utilize complementary genetic and phar- macologic tools, in vivo and ex vivo studies (with isolated AMs), and pathway-specific inhibitors to pursue two Specific Aims: 1) Ontogeny and transcriptional control of AM renewal, and 2) Role of GM-CSF regulated mitochondrial metabolism in AM renewal. The expected results will inform cellular and molecular mechanism(s) by which GM-CSF regulates AM population size and will lay the foundation for developing novel therapeutic strategies to modulate AM population size. The proposed research is innovative, in my opinion, because it challenges the previously widely-held concept of AMs as short-lived, non-dividing cells replenished from circulating monocytes (regulated by M-CSF) – and instead posits that AM population size is maintained by homeostatic self-renewal mediated by GM-CSF threshold-triggered/concentration-de- pendent, niche-limited proliferation of mature (long-lived) AMs. My novel preliminary data identified GM-CSF dependent regulation of mitochondrial homeostasis as a molecular mechanism for AM self-renewal. In addition, utilization of novel mouse models and novel methodologies will enable determination of how GM-CSF regulation of mitochondrial homeosta- sis regulates AM proliferation and will identify the regulatory genes and their downstream targets responsible for long- term maintenance of AMs. The proposed research is significant because it will advance our knowledge of a critical pulmo- nary hormone (GM-CSF) by informing the mechanism(s) by which GM-CSF regulates the long-term maintenance of endog- enous and transplanted AMs and inform us on the therapeutic mechanism of action of PMT, a novel cell therapy in devel- opment to treat patients with hereditary pulmonary alveolar proteinosis and potentially other lung diseases.


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	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Lung Diseases Research	000	4	11/5/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $529,995 )
2025	2025	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Lung Diseases Research	001	4	8/12/2025	NON-COMPETING CONTINUATION	$52,999
2025	2025	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Lung Diseases Research	000	4	11/15/2024	NON-COMPETING CONTINUATION	$476,996
														Subtotal = $529,995

Issue Date FY: 2024 ( Subtotal = $522,665 )
2024	2024	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Lung Diseases Research	000	3	11/8/2023	NON-COMPETING CONTINUATION	$479,997
2024	2024	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Lung Diseases Research	001	3	6/24/2024	NON-COMPETING CONTINUATION	$42,668
														Subtotal = $522,665

Issue Date FY: 2023 ( Subtotal = $540,046 )
2023	2023	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Lung Diseases Research	001	2	2/11/2023	NON-COMPETING CONTINUATION	$54,005
2023	2023	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Lung Diseases Research	000	2	11/17/2022	NON-COMPETING CONTINUATION	$486,041
														Subtotal = $540,046

Issue Date FY: 2022 ( Subtotal = $545,299 )
2022	2022	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Lung Diseases Research	000	1	11/26/2021	NEW	$545,299
														Subtotal = $545,299

Grand Total All Awards = $2,138,005

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Role of GM-CSF in Alveolar Macrophage Self-Renewal

Award Number: R01HL149743

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2021

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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