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Genetics, Epigenetics, and Post-translational Modifications and the Development of Ventilator Induced Lung Injury (VILI)

Award Number: P01HL134610
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROGRAM SUMMARY Mechanical ventilation, a life-saving intervention in critically ill patients with respiratory failure due to acute respiratory distress syndrome (ARDS), also creates excessive mechanical stress that augments lung injury, a syndrome known as ventilator-induced lung injury (VILI). The pathobiology of VILI and ARDS share many inflammatory features including increases in lung vascular permeability due to loss of endothelial cell (EC) barrier integrity. Insights into VILI pathobiology have been incremental with no viable therapies realized. This PPG intensely focuses on increasing our understanding of: i) the transcription factors that relay the effects of excessive mechanical stress; ii) the molecular signaling pathways that lead to EC injury, including initial activation of a mechanosensitive Ca2+-regulatory receptor, transient receptor potential cation channel subfamily V member 4 (TRPV4); iii) post translational modifications (PTMs) that influence key signaling pathways involved in VILI responses; iv) genetic and epigenetic influences in key target genes involved in VILI responses; and v) novel therapeutic strategies for VILI. The key novel genes that comprise the focus of each Project were identified by our genomic–intensive approaches and selected for their capacity to contribute to a spectrum of VILI responses from VILI-induced lung inflammation, increased vascular permeability and injury (Projects #1 and #2); to VILI resolution with restoration of lung vascular barrier integrity (Project #3). These strategies are integrated across our three PPG projects and represent the thematic underpinnings of this PPG. Studies will be conducted by an outstanding group of gifted and interactive translational scientists. Project #1 will examine the NF-¿B- dependent mechanisms (including protein nitration) by which VILI downregulates expression of SOX18, a critical lung vascular barrier-protective transcription factor (TF), and the key tight junction protein, claudin 5. The influence of the mechanosensitive receptor, TRPV4 on mitochondrial ROS and mechanical stress-associated TFs such as HIF2a will be explored. Project #2 will extend novel insights regarding the critical role of secreted extracellular NAMPT (eNAMPT), a nicotinamide phosphoribosyltransferase, in VILI and ARDS. Excessive mechanical stress induces NAMPT expression and eNAMPT ligates TLR4 (Toll-like receptor 4) to induce NF-¿B signaling and inflammatory lung injury. Project #2 will interrogate novel mechanisms of NAMPT secretion, the influence of NAMPT/TLR4 SNPs, and NAMPT and TLR4 as therapeutic targets. Project #3 will interrogate genetic and epigenetic regulation of mechanical stress-mediated sphingosine 1-phosphate receptor expression (S1PR1, S1PR3) and the role of VILI-induced nitration of Rac1 and RhoA GTPases in lung vascular barrier regulation. The synergy derived from the interaction between individual Projects, as well as with our scientific Cores, with enviable expertise in molecular biology (B), genetic epidemiology (B), pre-clinical models of disease (C), and protein chemistry & Biophyics (D), will advance our programmatic approaches and promote the development of novel, individualized therapies to attenuate VILI especially in populations at risk for ARDS.


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: 2022 ( Subtotal = $2,258,774 )
2022	2022	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Lung Diseases Research	002	6	4/27/2022	NON-COMPETING CONTINUATION	$2,258,774
2022	2021	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Lung Diseases Research	001	5	12/1/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$2,080,830
2022	2021	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Lung Diseases Research	004	5	5/11/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$237,866
2022	2021	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Lung Diseases Research	000	4	11/30/2021	NON-COMPETING CONTINUATION	-$2,080,830
2022	2021	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Lung Diseases Research	003	4	5/11/2022	NON-COMPETING CONTINUATION	-$237,866
														Subtotal = $2,258,774

Issue Date FY: 2021 ( Subtotal = $2,325,523 )
2021	2021	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Lung Diseases Research	001	4	5/15/2021	NON-COMPETING CONTINUATION	$232,550
2021	2021	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Lung Diseases Research	000	4	1/29/2021	NON-COMPETING CONTINUATION	$2,092,973
														Subtotal = $2,325,523

Issue Date FY: 2020 ( Subtotal = $2,325,523 )
2020	2020	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Lung Diseases Research	000	3	2/3/2020	NON-COMPETING CONTINUATION	$2,325,523
														Subtotal = $2,325,523

Issue Date FY: 2019 ( Subtotal = $2,325,523 )
2019	2019	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Lung Diseases Research	000	2	6/18/2019	NON-COMPETING CONTINUATION	$2,325,523
2019	2019	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Lung Diseases Research	001	2	7/26/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $2,325,523

Issue Date FY: 2018 ( Subtotal = $2,325,523 )
2018	2018	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Lung Diseases Research	000	1	2/2/2018	NEW	$2,325,523
														Subtotal = $2,325,523

Grand Total All Awards = $11,560,866

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Genetics, Epigenetics, and Post-translational Modifications and the Development of Ventilator Induced Lung Injury (VILI)

Award Number: P01HL134610

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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