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Role of MIF and CD74 in the pathogenesis of emphysema

Award Number: R01HL155948
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Role of MIF and CD74 in the pathogenesis of emphysema - PROJECT SUMMARY Emphysema is a common pathologic manifestation of Chronic Obstructive Pulmonary Disease (COPD), the fourth leading cause of death in the United States. The most important modifiable risk factor for emphysema is chronic exposure to cigarette smoke (CS). Yet, not all smokers develop emphysema and, therefore, cellular responses to CS are important mechanisms underlying disease progression. Our long-term goal is to define the cellular responses to CS and oxidative stress that protect the lung from emphysema. We have identified a cytoprotective role for the innate immune cytokine Macrophage Migration Inhibitory (MIF). MIF decreases oxidative stress and consequences of oxidative stress (e.g. cellular senescence and apoptosis) in lung endothelial cells, and mice with a genetic deletion of Mif are susceptible to emphysema. MIF is secreted in response to CS, but, paradoxically, MIF is decreased in patients with severe COPD. Targeting MIF, or its downstream pathways, may be therapeutic. However, MIF is a pleiotropic molecule with broad regulatory effects. To translate MIF biology into therapy, it will be essential to dissect out its cytoprotective pathways. Our goal for this proposal is to determine the mechanisms through which MIF antagonizes the development of emphysema. Our preliminary data suggests MIF mediates its protective effects through its receptor CD74. Our hypothesis is MIF protects against the development of emphysema by mitigating CS-mediated endothelial senescence in a CD74 dependent manner. In Aim 1, we will define the mechanism through which the MIF-CD74 interaction reduces endothelial senescence. In Aim 2, we will determine the role of endothelial CD74 in regulating susceptibility to emphysema. In Aim 3, we will determine the therapeutic potential of targeting MIF-CD74 interactions in emphysema. Completion of these aims will significantly advance our understanding of the pathogenesis of emphysema and may identify precision-based approaches based on MIF biology for treating patients with emphysema.


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	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Lung Diseases Research	000	5	10/21/2025	NON-COMPETING CONTINUATION	$0
2026	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Lung Diseases Research	001	5	3/14/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $684,815 )
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Lung Diseases Research	001	5	8/5/2025	NON-COMPETING CONTINUATION	$68,481
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Lung Diseases Research	000	5	1/3/2025	NON-COMPETING CONTINUATION	$616,334
														Subtotal = $684,815

Issue Date FY: 2024 ( Subtotal = $671,119 )
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Lung Diseases Research	001	4	6/26/2024	NON-COMPETING CONTINUATION	$54,785
2024	2024	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Lung Diseases Research	000	4	1/8/2024	NON-COMPETING CONTINUATION	$616,334
														Subtotal = $671,119

Issue Date FY: 2023 ( Subtotal = $684,815 )
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Lung Diseases Research	000	3	11/25/2022	NON-COMPETING CONTINUATION	$616,334
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Lung Diseases Research	001	3	3/10/2023	NON-COMPETING CONTINUATION	$68,481
														Subtotal = $684,815

Issue Date FY: 2022 ( Subtotal = $684,815 )
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Lung Diseases Research	000	2	12/22/2021	NON-COMPETING CONTINUATION	$616,333
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Lung Diseases Research	001	2	6/13/2022	NON-COMPETING CONTINUATION	$68,482
														Subtotal = $684,815

Issue Date FY: 2021 ( Subtotal = $684,815 )
2021	2021	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Lung Diseases Research	000	1	12/30/2020	NEW	$616,333
2021	2021	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Lung Diseases Research	001	1	6/19/2021	NEW	$68,482
														Subtotal = $684,815

Grand Total All Awards = $3,410,379

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Role of MIF and CD74 in the pathogenesis of emphysema

Award Number: R01HL155948

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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