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COPD cachexia: deciphering the impact of antioxidants, iron and mitochondrial function using 'omics approaches

Award Number: R01HL153460
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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SUMMARY Chronic Obstructive Pulmonary Disease (COPD) is the fourth leading cause of death in the United States with mortality continuing to rise despite advances in medicine. Cachexia, a form of muscle wasting, is a debilitating co-morbidity whose prevalence increases with severity of COPD. But, cachexia still occurs among COPD patients with milder disease severity. Cachexia is most often thought of with respect to cancer. However, by population prevalence there are more COPD patients with cachexia than cancer patients with cachexia. Yet there have been few studies investigating the etiology of COPD cachexia underscoring the need for investigations of COPD cachexia and weight-loss. Accumulating data including our own points to a role for iron toxicity in the etiology of COPD cachexia. Heme is an essential component of mitochondrial cytochromes providing protection from reactive oxygen species (ROS). Defects in heme biosynthesis cause buildup of free iron, ROS and mitochondrial dysfunction. Buildup of free iron leads to iron toxicity and production of ROS particularly in the absence of adequate intake of antioxidants such as Vitamins E. As such, our overarching hypothesis is iron toxicity in COPD cachexia is driven by impaired antioxidant and mitochondrial function. This study has three specific aims: 1) To determine whether genomic variation associated with the absorption and regulation of Vitamin E is more common in COPD cachexia; 2) To assess whether plasma Vitamin E in subjects with COPD cachexia are associated with impaired mitochondrial function; Exploratory Aim) To test whether iron induced transcriptional dysregulation signatures in myoblasts are preserved in transcriptomics signatures associated with COPD cachexia in skeletal muscle biopsies. Elucidating mechanisms of mitochondrial dysfunction in COPD cachexia has the potential to aid the development of therapeutics targeting mitochondrial oxidative stress. As future research, we plan to test whether ‘omic regions and metabolites identified as associated with COPD cachexia directly effect pathways involved with Vitamin E and mitochondrial function using targeted assays in myoblasts or other appropriate systems.


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: 2024 ( Subtotal = $659,276 )
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	000	4	6/10/2024	NON-COMPETING CONTINUATION	$659,276
														Subtotal = $659,276

Issue Date FY: 2023 ( Subtotal = $642,195 )
2023	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	000	3	4/25/2023	NON-COMPETING CONTINUATION	$642,195
2023	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	001	2	5/19/2023	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $642,195

Issue Date FY: 2022 ( Subtotal = $1,065,821 )
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	002	2	8/18/2022	SUPPLEMENT FOR EXPANSION	$111,375
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	001	2	8/5/2022	NON-COMPETING CONTINUATION	$643,727
2022	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	000	1	11/3/2021	NEW	$310,719
														Subtotal = $1,065,821

Issue Date FY: 2021 ( Subtotal = $666,481 )
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	000	1	6/10/2021	NEW	$666,481
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	001	1	7/28/2021	NEW	$0
														Subtotal = $666,481

Grand Total All Awards = $3,033,773

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COPD cachexia: deciphering the impact of antioxidants, iron and mitochondrial function using 'omics approaches

Award Number: R01HL153460

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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