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TRPC4-DEPENDENT CYTOSOLIC CALCIUM SIGNALS COORDINATE INTERENDOTHELIAL FORCES THAT ELICIT GAP FORMATION

Award Number: F32HL144040
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/01/2018
PERIOD OF PERFORMANCE END DATE: 06/04/2021

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TRPC4-DEPENDENT CYTOSOLIC CALCIUM SIGNALS COORDINATE INTERENDOTHELIAL FORCES THAT ELICIT GAP FORMATION - Project Summary Acute lung injury is a disorder of acute inflammation that causes disruption of the pulmonary endothelial barrier and contributes a significant amount of morbidity and mortality in the intensive care unit. Endothelial barrier integrity is critically determined by endothelial cytosolic calcium ion (Ca2+) transients that are activated by the plasma membrane store-operated Ca2+ entry (ISOC) channels. One of the channel subunits, canonical transient receptor potential 4 (TRPC4) protein, critically regulates channel activation and Ca2+ influx. Elevation of cytosolic Ca2+ is sufficient to induce interendothelial gaps in extra-alveolar segments and cause pulmonary edema. However, the mechanism by which TRPC4-dependent Ca2+ influx disrupts adherens junction and coordinates interendothelial forces is poorly understood and is the focus of this application. Cytosolic Ca2+ is not stable but rather fluctuates within a confluent endothelial monolayer. TRPC4 contributes to these basal cytosolic Ca2+ transients. Inflammatory agonists induce Ca2+ influx by activating the TRPC4 ISOC channel leading to a marked elevation of cytosolic Ca2+, which causes endothelial cell retraction and gap formation. However, it is unknown whether these TRPC4-dependent transient increases in cytosolic Ca2+ cause increases in the coordination of interendothelial forces, interendothelial gap formation, and lung edema. Inflammatory diseases are related to changes in mechanical properties of cells and tissues. Intercellular forces are spatially heterogeneous, highly cooperative, and aligned into force chains. During inflammation, disruption of the vascular endothelial barrier is partially initiated through cytoskeletal contraction of a group of cells. The resulting increased contractile forces propagate across neighboring cells via intercellular junctions to increase interendothelial force coordination and correlation, increase intracellular force alignment and extend force chains far outside the gap regions. A large accumulation of contractile forces may eventually exceed the maximum force that an adherens junction can withstand and cause the formation of an interendothelial gap. An interendothelial gap also may form at a tri-junctional (tricellular junction) point where force chains are misaligned and may pull the adherens junction apart. However, it is unknown how TRPC4-dependent cytosolic Ca2+ transients are related to interendothelial force correlation at baseline and after agonist challenge. This proposal tests the overall HYPOTHESIS that TRPC4 activation triggers unique cytosolic Ca2+ transients that are sufficient to increase interendothelial force correlation and promote gap formation, pulmonary permeability, and pulmonary edema.


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 = -$4,813 )
2023	2020	UNIVERSITY OF SOUTH ALABAMA	307 N UNIVERSITY BLVD	MOBILE	AL	36608	MOBILE	USA	Lung Diseases Research	000	3	11/23/2022	NON-COMPETING CONTINUATION	-$4,813
														Subtotal = -$4,813

Issue Date FY: 2022 ( Subtotal = -$24,793 )
2022	2020	UNIVERSITY OF SOUTH ALABAMA	307 UNIVERISTY BLVD 380 ADMINISTRATION BLDG	MOBILE	AL	36688	MOBILE	USA	Lung Diseases Research	000	3	4/18/2022	NON-COMPETING CONTINUATION	-$24,793
														Subtotal = -$24,793

Issue Date FY: 2020 ( Subtotal = $69,306 )
2020	2020	UNIVERSITY OF SOUTH ALABAMA	307 UNIVERISTY BLVD 380 ADMINISTRATION BLDG	MOBILE	AL	36688	MOBILE	USA	Lung Diseases Research	000	3	8/11/2020	NON-COMPETING CONTINUATION	$69,306
														Subtotal = $69,306

Issue Date FY: 2019 ( Subtotal = $63,746 )
2019	2019	UNIVERSITY OF SOUTH ALABAMA	307 UNIVERISTY BLVD 380 ADMINISTRATION BLDG	MOBILE	AL	36688	MOBILE	USA	Lung Diseases Research	000	2	8/16/2019	NON-COMPETING CONTINUATION	$63,746
														Subtotal = $63,746

Issue Date FY: 2018 ( Subtotal = $59,038 )
2018	2018	UNIVERSITY OF SOUTH ALABAMA	307 UNIVERISTY BLVD 380 ADMINISTRATION BLDG	MOBILE	AL	36688	MOBILE	USA	Lung Diseases Research	000	1	8/6/2018	NEW	$59,038
2018	2018	UNIVERSITY OF SOUTH ALABAMA	307 UNIVERISTY BLVD 380 ADMINISTRATION BLDG	MOBILE	AL	36688	MOBILE	USA	Lung Diseases Research	002	1	8/9/2018	NEW	$0
2018	2018	UNIVERSITY OF SOUTH ALABAMA	307 UNIVERISTY BLVD 380 ADMINISTRATION BLDG	MOBILE	AL	36688	MOBILE	USA	Lung Diseases Research	001	1	8/9/2018	NEW	$0
														Subtotal = $59,038

Grand Total All Awards = $162,484

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TRPC4-DEPENDENT CYTOSOLIC CALCIUM SIGNALS COORDINATE INTERENDOTHELIAL FORCES THAT ELICIT GAP FORMATION

Award Number: F32HL144040

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/01/2018

PERIOD OF PERFORMANCE END DATE: 06/04/2021

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