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Regulation of phosphodiesterases and cAMP signaling during the host-pathogen interaction in the pulmonary endothelium

Award Number: R01HL141473
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY/ABSTRACT Acute respiratory distress syndrome (ARDS) is an inflammatory lung disease associated with high morbidity/mortality and limited treatment options. A breakdown of pulmonary endothelial barrier function, leading to edema and impaired lung function, is a hallmark of ARDS. It is well established that stimulation of cAMP synthesis, such as with ß-adrenoceptor agonists, enhances endothelial barrier function and is protective in preclinical models of sterile lung injury such as upon LPS administration. However, clinical trials probing the utility of ß-agonists in ARDS have failed and the reasons remain unclear. Cyclic nucleotide phosphodiesterases (PDEs), the enzymes that degrade and inactivate cAMP, play a critical role in the regulation of cellular cAMP levels, the subcellular compartmentalization of these signals, and hence endothelial cell functions. Our preliminary data indicate that a single Type-4 PDE isoform, PDE4D, contributes the predominant portion of cAMP-hydrolytic capacity in the pulmonary endothelium and is tightly regulated under physiologic conditions. P.aeruginosa (PA) is a common cause of nosocomial pneumonia that can progress to sepsis and ARDS. We observed that during the host-pathogen interaction, distinct PA virulence factors induce PDE4D activation, resulting in a suppression and dysregulation of endothelial cAMP signals. Specifically, the bacterial exotoxin cyclase ExoY promotes a PKA-mediated phosphorylation and activation of PDE4D that alters endothelial cAMP signaling. In addition, PA infection can induce a PKA-independent, but type-3 secretion system- and flagellin-dependent PDE4D regulation that results in activation and subcellular relocalization of the enzyme. With this proposal, we will define the pathways by which PA virulence factors alter PDE4D functions and its contribution to endothelial barrier disruption and lung injury. We will test the idea that PA-induced PDE4D activation correlates with health outcomes in patients with PA-associated ARDS, and that, conversely, inhibition of PDE4 is endothelial barrier protective. We will test the idea that aberrant PDE4 activation limits the therapeutic efficacy of ß-agonists in settings of PA-lung infection as well as other causes of ARDS. The PDE4 family comprises four genes and non-selective PDE4 inhibitors have established therapeutic effects in preclinical models of ARDS, but also induce side effects, such as emesis and nausea, that limit their clinical utility. Given the unique and non-overlapping physiological and pathophysiological roles of each PDE4 isoform, targeting individual PDE4 proteins can serve to dissect the therapeutically beneficial from the side effects of the PAN-PDE4 inhibitors available to date. To this end, we will determine whether selective ablation of PDE4D is protective in ex vivo and in vivo models of PA-lung injury, paving the way for development of PDE4D-selective inhibitors as ARDS therapeutics with an improved safety profile compared to the non- selective PDE4 inhibitors available to date.


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 = $0 )
2024	2021	UNIVERSITY OF SOUTH ALABAMA	307 N UNIVERSITY BLVD	MOBILE	AL	36608	MOBILE	USA	Lung Diseases Research	000	4	1/11/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $378,245 )
2021	2021	UNIVERSITY OF SOUTH ALABAMA	307 UNIVERISTY BLVD 380 ADMINISTRATION BLDG	MOBILE	AL	36688	MOBILE	USA	Lung Diseases Research	000	4	3/25/2021	NON-COMPETING CONTINUATION	$378,245
														Subtotal = $378,245

Issue Date FY: 2020 ( Subtotal = $378,245 )
2020	2020	UNIVERSITY OF SOUTH ALABAMA	307 UNIVERISTY BLVD 380 ADMINISTRATION BLDG	MOBILE	AL	36688	MOBILE	USA	Lung Diseases Research	001	3	6/5/2020	NON-COMPETING CONTINUATION	$0
2020	2020	UNIVERSITY OF SOUTH ALABAMA	307 UNIVERISTY BLVD 380 ADMINISTRATION BLDG	MOBILE	AL	36688	MOBILE	USA	Lung Diseases Research	000	3	3/27/2020	NON-COMPETING CONTINUATION	$378,245
														Subtotal = $378,245

Issue Date FY: 2019 ( Subtotal = $378,245 )
2019	2019	UNIVERSITY OF SOUTH ALABAMA	307 UNIVERISTY BLVD 380 ADMINISTRATION BLDG	MOBILE	AL	36688	MOBILE	USA	Lung Diseases Research	000	2	3/27/2019	NON-COMPETING CONTINUATION	$378,245
														Subtotal = $378,245

Issue Date FY: 2018 ( Subtotal = $391,120 )
2018	2018	UNIVERSITY OF SOUTH ALABAMA	380 ADMINISTRATION BUILDING	MOBILE	AL	36688	MOBILE	USA	Lung Diseases Research	000	1	2/1/2018	NEW	$391,120
														Subtotal = $391,120

Grand Total All Awards = $1,525,855

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Regulation of phosphodiesterases and cAMP signaling during the host-pathogen interaction in the pulmonary endothelium

Award Number: R01HL141473

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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