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Role of titin in the pathophysiology of diaphragm weakness during mechanical ventilation

Award Number: R01HL121500
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2014
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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Role of titin in the pathophysiology of diaphragm weakness during mechanical ventilation - Summary Our long-term goal is to understand diaphragm contractility in health and disease, and the role of titin therein. The diaphragm muscle drives respiration and is constantly subjected to mechanical loading. Changes in mechanical loading rapidly affect diaphragm contractility, e.g., within hours of diaphragm unloading during mechanical ventilation (MV) in ICU patients, severe diaphragm weakness ensues, contributing to difficult ventilator weaning. The pathophysiology of diaphragm weakness is incompletely understood. In the proposal at hand, we will study the role of depressed interactions between myosin and actin, the two key contractile proteins in myofibers, and the role of titin in force depression. Our pilot data suggest that unloading of the diaphragm causes the myosin motors to adopt the so-called ‘super-relaxed state’ (SRX). Once in the SRX state, less myosin motors are available for binding to actin, and less force can be generated. We will also study the role of the giant protein titin in releasing myosin from the SRX state and investigate whether during MV-induced unloading of the diaphragm, this mechanism is perturbed. Aim 1 will determine the SRX state of myosin in the diaphragm of ventilated ICU patients. We will use our diaphragm biopsies of ICU patients to study the contractile force of diaphragm myofibers and determine the number of myosin motors that attach to actin during activation. We will combine mechanics with X-ray diffraction and biochemical assays to resolve with nanometer resolution the position of myosin motors relative to actin during activation and the proportion of myosin in the SRX state. In Aim 2 we will determine the role of posttranslational modifications in the SRX of myosin. Phosphorylation of regulatory light chains (RLC) regulates the SRX state of myosin and we will apply mass-spectrometry on the diaphragm biopsies to determine the phospho-proteome, and we will establish whether there is a cause-and-effect relation between RLC phosphorylation and SRX by performing RLC exchange experiments into patients’ myofibers. To critically test whether changes in RLC are caused by diaphragm inactivity, we will ventilated healthy rats, and study RLC phosphorylation. Aim 3 will determine whether, in addition to RLC phosphorylation, direct mechanical effects of titin on myosin induce SRX. Titin-based passive tension strains the myosin filament which regulates the SRX state. We will study whether the reduction in titin-based passive tension, due to diaphragm unloading during MV, reduces the strain in the myosin filament and increases SRX. We will use mouse models with genetically engineered increased or decreased titin-based passive tension and study the effect of MV on the SRX state of myosin. The innovation of this proposal lies in the novel research foci and guiding hypotheses, unique diaphragm biopsies from patients, and its novel tools and mouse models, The proposal’s integrative approach is expected to lead to a major step forward in our understanding of diaphragm function and titin’s role therein.


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 = $586,463 )
2025	2025	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Lung Diseases Research	001	12	9/3/2025	NON-COMPETING CONTINUATION	$586,463
2025	2022	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Lung Diseases Research	000	9	2/19/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $586,463

Issue Date FY: 2024 ( Subtotal = $587,842 )
2024	2024	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Lung Diseases Research	000	11	9/12/2024	NON-COMPETING CONTINUATION	$587,842
														Subtotal = $587,842

Issue Date FY: 2023 ( Subtotal = $556,120 )
2023	2023	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Lung Diseases Research	000	10	8/3/2023	COMPETING CONTINUATION	$556,120
														Subtotal = $556,120

Issue Date FY: 2022 ( Subtotal = $506,920 )
2022	2022	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Lung Diseases Research	000	9	7/29/2022	NON-COMPETING CONTINUATION	$506,920
														Subtotal = $506,920

Issue Date FY: 2021 ( Subtotal = $506,920 )
2021	2021	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Lung Diseases Research	000	8	6/25/2021	NON-COMPETING CONTINUATION	$506,920
														Subtotal = $506,920

Issue Date FY: 2020 ( Subtotal = $506,920 )
2020	2020	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Lung Diseases Research	002	7	9/3/2020	NON-COMPETING CONTINUATION	$506,920
2020	2019	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Lung Diseases Research	001	6	2/15/2020	COMPETING CONTINUATION	$151
2020	2018	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Lung Diseases Research	000	5	2/15/2020	NON-COMPETING CONTINUATION	-$151
														Subtotal = $506,920

Issue Date FY: 2019 ( Subtotal = $506,920 )
2019	2019	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Lung Diseases Research	001	6	6/28/2019	COMPETING CONTINUATION	$506,920
2019	2018	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Lung Diseases Research	000	5	6/27/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $506,920

Issue Date FY: 2018 ( Subtotal = $371,244 )
2018	2018	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Lung Diseases Research	001	5	6/16/2018	NON-COMPETING CONTINUATION	$7,425
2018	2018	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Lung Diseases Research	000	5	1/1/2018	NON-COMPETING CONTINUATION	$363,819
														Subtotal = $371,244

Issue Date FY: 2017 ( Subtotal = $371,244 )
2017	2017	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Lung Diseases Research	000	4	12/1/2016	NON-COMPETING CONTINUATION	$371,244
														Subtotal = $371,244

Issue Date FY: 2016 ( Subtotal = $371,244 )
2016	2016	UNIVERSITY OF ARIZONA	POST OFFICE BOX 3308	TUCSON	AZ	85722		USA	Lung Diseases Research	000	3	12/31/2015	NON-COMPETING CONTINUATION	$365,675
2016	2016	UNIVERSITY OF ARIZONA	POST OFFICE BOX 3308	TUCSON	AZ	85722		USA	Lung Diseases Research	001	3	2/1/2016	NON-COMPETING CONTINUATION	$5,569
														Subtotal = $371,244

Issue Date FY: 2015 ( Subtotal = $365,675 )
2015	2015	UNIVERSITY OF ARIZONA	POST OFFICE BOX 3308	TUCSON	AZ	85722		USA	Lung Diseases Research	000	2	12/6/2014	NON-COMPETING CONTINUATION	$334,119
2015	2015	UNIVERSITY OF ARIZONA	POST OFFICE BOX 3308	TUCSON	AZ	85722		USA	Lung Diseases Research	001	2	2/23/2015	NON-COMPETING CONTINUATION	$31,556
														Subtotal = $365,675

Issue Date FY: 2014 ( Subtotal = $371,244 )
2014	2014	UNIVERSITY OF ARIZONA	POST OFFICE BOX 3308	TUCSON	AZ	85722		USA	Lung Diseases Research	000	1	12/30/2013	NEW	$334,120
2014	2014	UNIVERSITY OF ARIZONA	POST OFFICE BOX 3308	TUCSON	AZ	85722		USA	Lung Diseases Research	001	1	3/8/2014	NEW	$37,124
														Subtotal = $371,244

Grand Total All Awards = $5,608,756

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Role of titin in the pathophysiology of diaphragm weakness during mechanical ventilation

Award Number: R01HL121500

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2014

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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