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Determinants of 5 Year Progression of Muscle Dysfunction and Inactivity in COPDGene Participants.

Award Number: R01HL151452
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2020
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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Determinants of 5 Year Progression of Muscle Dysfunction and Inactivity in COPDGene Participants. - PROJECT SUMMARY Chronic obstructive pulmonary disease (COPD) is destruction of lung tissue and/or thickening of lung airways. It is the fourth leading cause of death in the USA. COPD is progressive and characterized by chronic inflammation and shortness of breath on exertion, which leads to physical inactivity and skeletal muscle dysfunction. Survival rate in COPD is more closely associated with exercise capacity than the severity of lung disease. A key determinant of exercise capacity is the ability of skeletal muscle mitochondria to sustain cellular energy delivery (termed, oxidative capacity). We recently applied a noninvasive near-infrared light-based method to assess muscle oxidative capacity in 245 smokers with and without COPD: the COPDGene ancillary Muscle Health Study. We showed that severe COPD patients have a 40% lower muscle oxidative capacity than smokers or never smokers with normal lung function. Yet, many questions remain about characteristics and mechanisms behind the loss of muscle oxidative capacity in COPD. The current proposal will follow-up with 200 of the Muscle Health Study participants to determine for the first time the rate of decline in lower limb skeletal muscle oxidative capacity over 5 years. Using the individual genetics, triaxial accelerometer measured daily physical activity, body composition measured by DXA, and 808 other clinical variables collected in the COPDGene parent study, we will identify clinical, behavioral and genetic variables that associate with the 5-year decline in skeletal muscle oxidative capacity. In addition, quadriceps muscle biopsy samples from 20 COPD patients with the fastest decline and 20 with the slowest decline in muscle oxidative capacity, identified by the near-infrared based noninvasive assessment, will be used to discover how gene expression is altered by the disease. DNA methylation and expression of small and large RNAs, including small non-coding RNAs from the mitochondrial genome (mitosRNAs), will be probed. These highly specific approaches will provide a detailed profile of mitochondrial and nuclear genes and/or gene networks underlying the causes of derangements in the lower limb skeletal muscles of COPD patients. The decline in muscle oxidative capacity impairs exercise tolerance and predisposes patients to chronic diseases such as cardiovascular disease, diabetes and obesity, each of which increases risk of premature death. The current proposal will be the first to determine how loss of muscle oxidative capacity progresses in COPD, and answer fundamental questions about the nature of the associations among mitochondrial dysfunction, sedentary lifestyle and poor outcomes in COPD patients. Our findings will guide efforts to create new therapeutic strategies to prevent skeletal muscle dysfunction, increase autonomy, hospital free survival and quality-of-life in COPD.


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	2023	LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER	1124 W CARSON ST BLDG MRL	TORRANCE	CA	90502	LOS ANGELES	USA	Lung Diseases Research	000	4	6/13/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $377,856 )
2023	2023	LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER	1124 W CARSON ST	TORRANCE	CA	90502	LOS ANGELES	USA	Lung Diseases Research	000	4	3/10/2023	NON-COMPETING CONTINUATION	$377,856
														Subtotal = $377,856

Issue Date FY: 2022 ( Subtotal = $409,674 )
2022	2022	LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER	1124 WEST CARSON ST.	TORRANCE	CA	90502	LOS ANGELES	USA	Lung Diseases Research	000	3	1/19/2022	NON-COMPETING CONTINUATION	$340,776
2022	2022	LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER	1124 WEST CARSON ST.	TORRANCE	CA	90502	LOS ANGELES	USA	Lung Diseases Research	001	3	1/20/2022	SUPPLEMENT FOR EXPANSION	$31,033
2022	2022	LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER	1124 W CARSON ST	TORRANCE	CA	90502	LOS ANGELES	USA	Lung Diseases Research	002	3	6/14/2022	NON-COMPETING CONTINUATION	$37,865
														Subtotal = $409,674

Issue Date FY: 2021 ( Subtotal = $458,801 )
2021	2021	LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER	1124 WEST CARSON ST.	TORRANCE	CA	90502	LOS ANGELES	USA	Lung Diseases Research	002	2	6/4/2021	NON-COMPETING CONTINUATION	$38,859
2021	2021	LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER	1124 WEST CARSON ST.	TORRANCE	CA	90502	LOS ANGELES	USA	Lung Diseases Research	001	2	4/29/2021	SUPPLEMENT FOR EXPANSION	$70,220
2021	2021	LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER	1124 WEST CARSON ST.	TORRANCE	CA	90502	LOS ANGELES	USA	Lung Diseases Research	000	2	2/3/2021	NON-COMPETING CONTINUATION	$349,722
														Subtotal = $458,801

Issue Date FY: 2020 ( Subtotal = $402,264 )
2020	2020	LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER	1124 WEST CARSON ST.	TORRANCE	CA	90502	LOS ANGELES	USA	Cardiovascular Diseases Research	000	1	1/17/2020	NEW	$402,264
														Subtotal = $402,264

Grand Total All Awards = $1,648,595

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Determinants of 5 Year Progression of Muscle Dysfunction and Inactivity in COPDGene Participants.

Award Number: R01HL151452

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2020

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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