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HDAC6 regulates cigarette smoke-induced endothelial barrier dysfunction and lung injury

Award Number: R01HL130230
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2016
PERIOD OF PERFORMANCE END DATE: 05/31/2022

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HDAC6 regulates cigarette smoke-induced endothelial barrier dysfunction and lung injury - Cigarette smoke (CS) affects 1 billion people worldwide and causes 6 million premature deaths from associated diseases each year. Acute lung injury (ALI)/ acute respiratory distress syndrome (ARDS) is a life- threatening condition with 40% mortality. Emerging epidemiology studies have shown that CS predisposes lungs to infections and increases the likelihood of ALI/ ARDS. However, the mechanism of adverse effects of CS on ALI is unknown. There is an urgent need for strategies to prevent and treat ALI/ ARDS in smokers. The objectives of this application is to use human lung microvascular endothelial cells (LMVEC) and preclinical animal models to identify mechanisms by which CS impairs pulmonary endothelial barrier function and increases vulnerability to ALI after bacterial infection and to develop strategies to prevent and restore endothelial barrier function and ALI in susceptible populations. This study uses state-of-art technologies and comprehensive approaches to address a central hypothesis that CS increases endothelial cell permeability and predisposes lungs to ALI after infection by a mechanism in which oxidants from CS and mitochondria cause Akt oxidation and subsequent GSK3β-dependent activation of histone deacetylase 6 (HDAC6), this results in microtubule deacetylation, leading to translocation of dynamin-related protein (Drp)1 to mitochondria, culminating in mitochondrial fission and dysfunction and subsequent release of mitochondrial damage- associated molecular patterns (mtDAMPs). Aim 1: We will first determine the role of HDAC6 in CS priming for ALI after Pseudomonas aeruginosa infection by using global HDAC6 knockout mice, endothelium-specific lentiviral HDAC6 miRNA silencing in vivo, and LMVEC isolated from HDAC6 knockout mice; we will then determine the mechanism by which CS exposure leads to HDAC6 activation. Aim 2: We will determine the role of HDAC6 in CS-induced mitochondrial fission and dysfunction and their roles in mediating increased endothelial permeability and priming for ALI after P. aeruginosa infection. We will first characterize the effects of CS exposure on Drp1 translocation and on mitochondrial fission, fusion, function, and release of mtDNA in vitro and in vivo; we will then determine the effect of blocking HDAC6 or α-tubulin deacetylation on the adverse effects of CS on mitochondria in vitro and in vivo; finally, we will determine the roles of mitochondrial fission, mitochondrial ROS and mtDAMPs in CS-induced increased endothelial permeability in vitro and CS priming for ALI in vivo. This study will provide innovative insights into the effect of CS on lung endothelial barrier function. Establishment of the links among HDAC6, mitochondrial fission and mtDAMPs may result in new therapeutic approaches to CS-induced vascular injury in the lung and potentially also in the systemic circulation.


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: 2023 ( Subtotal = $0 )
2023	2019	OCEAN STATE RESEARCH INSTITUTE INC	830 CHALKSTONE AVE	NORTH PROVIDENCE	RI	02908	PROVIDENCE	USA	Lung Diseases Research	000	4	9/6/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2019	OCEAN STATE RESEARCH INSTITUTE, INC.	830 CHALKSTONE AVE BLDG 35	PROVIDENCE	RI	02908	PROVIDENCE	USA	Lung Diseases Research	000	4	5/3/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2019	OCEAN STATE RESEARCH INSTITUTE, INC.	830 CHALKSTONE AVE BLDG 35	PROVIDENCE	RI	02908	PROVIDENCE	USA	Lung Diseases Research	000	4	4/28/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $321,750 )
2019	2019	OCEAN STATE RESEARCH INSTITUTE, INC.	830 CHALKSTONE AVE BLDG 35	PROVIDENCE	RI	02908	PROVIDENCE	USA	Lung Diseases Research	000	4	6/19/2019	NON-COMPETING CONTINUATION	$321,750
														Subtotal = $321,750

Issue Date FY: 2018 ( Subtotal = $321,750 )
2018	2018	BROWN UNIVERSITY IN PROVIDENCE IN THE STATE OF RHODE ISLAND AND PROVIDENCE PLANTATIONS	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Lung Diseases Research	000	3	6/11/2018	NON-COMPETING CONTINUATION	$321,750
														Subtotal = $321,750

Issue Date FY: 2017 ( Subtotal = $321,750 )
2017	2017	BROWN UNIVERSITY IN PROVIDENCE IN THE STATE OF RHODE ISLAND AND PROVIDENCE PLANTATIONS	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Lung Diseases Research	000	2	6/2/2017	NON-COMPETING CONTINUATION	$321,750
														Subtotal = $321,750

Issue Date FY: 2016 ( Subtotal = $321,750 )
2016	2016	OCEAN STATE RESEARCH INSTITUTE INC	830 CHALKSTONE AVENUE	PROVIDENCE	RI	02908	PROVIDENCE	USA	Lung Diseases Research	000	1	6/3/2016	NEW	$321,750
														Subtotal = $321,750

Grand Total All Awards = $1,287,000

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HDAC6 regulates cigarette smoke-induced endothelial barrier dysfunction and lung injury

Award Number: R01HL130230

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2016

PERIOD OF PERFORMANCE END DATE: 05/31/2022

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