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Impact of Diet Induced Obesity on Acute Lung Injury

Award Number: K08HL157728
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 01/15/2022
PERIOD OF PERFORMANCE END DATE: 01/17/2025

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Impact of Diet Induced Obesity on Acute Lung Injury - PROJECT SUMMARY Obesity afflicts 42% of the adults in the United States and is associated with significant deleterious health effects. Acute respiratory distress syndrome (ARDS) represents a final pathway of acute lung injury (ALI) arising from infectious, such as pneumonia, or sterile, such as ventilator induced lung injury, etiologies, and is associated with high mortality. Obese patients are at increased risk of developing ARDS. This proposal addresses the critical need to better understand the mechanisms that underlie the increased susceptibility of obese patients to ARDS. We have shown in a murine model of high fat diet that obesity results in more severe ALI in sterile and infectious models of ARDS. Obesity is characterized by increased fatty acid (FA) release that exceeds metabolic demands. Although FA are important for the physiologic regulation of a number of processes, high levels are deleterious. We have found increased free FA in the lung of obese mice after infectious and sterile ALI. FA are broken down by means of oxidation for energy generation inside the mitochondria, whereas endogenous FA are synthesized de novo from acetyl coenzyme A. High fat diet was associated with increased lung expression of carnitine palmitoyltransferase 1a (CPT1a), an essential rate limiting enzyme for oxidation, and decreased expression of fatty acid synthase (FASN), the enzyme catalyzing de novo FA synthesis, and of the mitochondrial fusion protein mitofusin 2 (MFN2) after ALI. Mitochondria alter size and shape via fission and fusion to meet cellular metabolic demands. Mitochondrial alterations in the alveolar epithelium have been implicated in ALI pathogenesis. We demonstrated that depletion of FASN in alveolar epithelial type 2 cells was associated with more severe ALI and impaired mitochondrial bioenergetics. In this proposal, we hypothesize high fat diet induced downregulation of mitochondrial fusion and lipid synthesis lead to impaired mitochondrial metabolisml after injury. Mitochondrial overload through excessive oxidation further exacerbates mitochondrial dysfunction. Aim 1 will investigate the role of FA utilization in the pathogenesis of experimental obesity induced ALI by using genetic and pharmacologic approaches to inhibit and enhance oxidation. Aim 2 will delineate the association between FASN regulation, mitochondrial dynamics and alveolar epithelial cell type 2 dysfunction in ALI with high fat diet using genetic approaches to inhibit FASN and MFN1/2 in a sterile and infectious model of ALI. Aim 3 will characterize dysregulated metabolic pathways based on body mass index (BMI) in patients with ARDS using plasma metabolomic profiling. These studies will provide insight into the interplay between obesity and ARDS and may uncover an unappreciated role for lipid metabolism in ALI. This proposal plays a central role in a career development plan for becoming a successful independent investigator focused on lung biology and lipid metabolism. Weill Cornell Medicine is an ideal environment in which to execute this training plan not only because of its excellent physical resources, but also because of its intellectual community of researchers with a track record of strong mentorship of early stage investigators.


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 = $22,002 )
2025	2025	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Lung Diseases Research	002	4	6/25/2025	NON-COMPETING CONTINUATION	-$145,938
2025	2025	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Lung Diseases Research	001	4	1/16/2025	NON-COMPETING CONTINUATION	$0
2025	2025	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Lung Diseases Research	000	4	12/17/2024	NON-COMPETING CONTINUATION	$167,940
														Subtotal = $22,002

Issue Date FY: 2024 ( Subtotal = $167,940 )
2024	2024	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Lung Diseases Research	001	3	8/23/2024	NON-COMPETING CONTINUATION	$0
2024	2024	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Lung Diseases Research	000	3	12/21/2023	NON-COMPETING CONTINUATION	$167,940
														Subtotal = $167,940

Issue Date FY: 2023 ( Subtotal = $167,940 )
2023	2023	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Lung Diseases Research	000	2	12/7/2022	NON-COMPETING CONTINUATION	$167,940
														Subtotal = $167,940

Issue Date FY: 2022 ( Subtotal = $221,940 )
2022	2022	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Lung Diseases Research	003	1	9/24/2022	NEW	$0
2022	2022	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	1	9/5/2022	SUPPLEMENT FOR EXPANSION	$54,000
2022	2022	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Lung Diseases Research	000	1	1/10/2022	NEW	$167,940
2022	2022	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Lung Diseases Research	001	1	1/27/2022	NEW	$0
														Subtotal = $221,940

Grand Total All Awards = $579,822

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Impact of Diet Induced Obesity on Acute Lung Injury

Award Number: K08HL157728

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 01/15/2022

PERIOD OF PERFORMANCE END DATE: 01/17/2025

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