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Metabolic Energy Crisis Signature Predicts Quality of Life in Survivors of Acute Respiratory Failure

Award Number: R21NR019338
ORGANIZATION: NATIONAL INSTITUTE OF NURSING RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2021
PERIOD OF PERFORMANCE END DATE: 04/30/2024

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Metabolic Energy Crisis Signature Predicts Quality of Life in Survivors of Acute Respiratory Failure - Project Summary/Abstract Survivors of acute respiratory failure (ARF) often face a daunting return to normal life as they have significant impairment of physical function. Over half of these patients are never able to return to work and often sustain significant skeletal muscle loss. Reliable algorithms to predict long-term physical function are currently unavailable. We previously described how metabolomics are predictive of acute outcomes in sepsis and ARF. Many of these metabolomic changes are related to dysfunction of β-oxidation, the citric acid cycle (TAC) and nicotinamide adenine dinucleotide (NADH) metabolism. Mitochondrial dysfunction is now considered to be a major driver of sepsis outcomes and may play a role in sepsis-induced muscle dysfunction. Furthermore, mitochondrial DNA (mtDNA) damage-associated molecular patterns (DAMPs) predicts patient outcomes in critical illness and trauma. We have developed a novel and innovative RNA target-bait capture deep sequencing and bioinformatics protocol for accurate quantitation and differentiation of mtDNA DAMPs and nuclear mitochondrial pseudogenes We hypothesize that mtDNA damage-associated molecular patterns (DAMPs) or metabolomic changes are reflective of mitochondrial-related bioenergetic status, and will also predict physical function in six-month survivors of ARF. In support of this hypothesis, we found in a small pilot study that mitochondrial related metabolites measured at patient discharge correlated with poor physical function in six- month survivors of ARF. In this study, we propose to expand upon the metabolomic and mtDNA results by leveraging patient data and plasma samples that were collected within the single center, randomized clinical trial at Wake Forest Baptist Medical Center (TARGET; ClinicalTrials.gov Identifier: NCT00976833). This study was designed to test if physical therapy initiated in the ICU reduced ICU length-of-stay and improved longterm quality- of-life in survivors. In Aim 1, we will establish that increased concentrations of mtDNA DAMPs in cell-free plasma predict physical function in survivors of ARF. Aim 2 will investigate the link between the concentration of mitochondrial-related bioenergetics metabolites and the abundance of mtDNA DAMPs in cell-free plasma. The results from this study will provide new pathophysiologic insight into the role of mtDNA DAMPs and mitochondrial-associated metabolites in ARF-induced poor physical function. New pharamcological therapies have the potential to improve physical function through improved mitochondrial function, biogenesis, and reduction of mtDNA DAMPs, while NAD-derivatives or androgenic steroid repletion could improve physical strength and function.


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 = -$492 )
2024	2022	UNIVERSITY OF SOUTH ALABAMA	307 N UNIVERSITY BLVD	MOBILE	AL	36608	MOBILE	USA	Nursing Research	000	2	7/29/2024	NON-COMPETING CONTINUATION	-$492
														Subtotal = -$492

Issue Date FY: 2022 ( Subtotal = $200,788 )
2022	2022	UNIVERSITY OF SOUTH ALABAMA	307 UNIVERISTY BLVD 380 ADMINISTRATION BLDG	MOBILE	AL	36688	MOBILE	USA	Nursing Research	000	2	4/29/2022	NON-COMPETING CONTINUATION	$200,788
														Subtotal = $200,788

Issue Date FY: 2021 ( Subtotal = $249,683 )
2021	2021	UNIVERSITY OF SOUTH ALABAMA	307 UNIVERISTY BLVD 380 ADMINISTRATION BLDG	MOBILE	AL	36688	MOBILE	USA	Nursing Research	000	1	4/9/2021	NEW	$249,683
														Subtotal = $249,683

Grand Total All Awards = $449,979

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Metabolic Energy Crisis Signature Predicts Quality of Life in Survivors of Acute Respiratory Failure

Award Number: R21NR019338

ORGANIZATION: NATIONAL INSTITUTE OF NURSING RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2021

PERIOD OF PERFORMANCE END DATE: 04/30/2024

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