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Purinergic Regulation of Veinous Endothelial Permeability

Award Number: R01HL137112
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/18/2018
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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Purinergic Regulation of Veinous Endothelial Permeability - || ABSTRACT Breakdown of the endothelial cell barrier is considered a defining pathological hallmark of multiple diseases. Indeed, sepsis accounts for more hospital deaths per year than any other condition in the United States, and the disease is currently devoid of any targeted pharmacological intervention. Critical to understanding how inflammation affects vascular barrier function is that endothelial cells throughout the circulatory system are not homogenous. Inflammation specifically affects vascular permeability through effects on the venous endothelium, whereas the arterial endothelium is not susceptible to inflammation-induced permeability and instead primarily regulates blood pressure. Thus, a mechanistic view of how venous endothelial barrier function is regulated is essential to human health and disease. Our current understanding of vascular barrier function does not account for endothelial heterogeneity and the unique cell adhesion and signaling pathways specific to each endothelial cell type. Purinergic signaling has been identified as a key regulator of endothelial permeability; however the cellular pathway allowing for simultaneous regulation of the purine response and tight junctions has not been explored. We hypothesize that the purine release channel pannexin (Panx)1 in venous endothelium is a component of a dynamic signaling nexus activated upon inflammatory stimuli such as sepsis. We will use three aims to test this concept. In Aim 1, we will identify kinase signaling pathways targeting Panx1 that regulate venous permeability. This aim will use novel mouse models with point mutations in Panx1 for post-translational modification and measure how these key modifications alter pathological responses to cecal ligation puncture (CLP) sepsis model, venous permeability, and ATP release. Aim 2, we will measure the impact of claudin11 (cldn)11 on the intracellular distribution of Panx1 and organization of other components required for purinergic signaling in response TNFa stimulated venous permeability. Based on our previous work, we found cldn11 to be uniquely expressed across the venous endothelium that was selectively broken down in response to TNFa/sepsis; this contrasted with claudin5. Here was posit cldn11 is a unique signaling hub due to its ability to be regulated by changes in calcium, and that property of the tight junction regulates Panx1 function on venous endothelium. Last, in Aim 3 we will determine roles for internalization and turnover of components of the Panx1/Cldn11 hub in regulation of venous permeability. Turnover and reseting the signaling complex is an important component to the cellular response to inflammation. In this aim we provide evidence that caveolin1 facilitates recycling of both Panx1 and cldn11 after inflammatory stimuli, and probe the mechanisms of how this may occur. The feasibility of accomplishing these aims is underscored by all proposed knockout mice being in hand, coupled with strong preliminary data and a highly productive previous funding cycle between the two investigators.


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 = $592,569 )
2025	2025	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cardiovascular Diseases Research	000	7	6/30/2025	NON-COMPETING CONTINUATION	$592,569
														Subtotal = $592,569

Issue Date FY: 2024 ( Subtotal = $655,687 )
2024	2024	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cardiovascular Diseases Research	002	6	5/23/2024	NON-COMPETING CONTINUATION	$655,687
2024	2023	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cardiovascular Diseases Research	001	5	11/21/2023	COMPETING CONTINUATION	$5,866
2024	2021	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cardiovascular Diseases Research	000	4	11/21/2023	NON-COMPETING CONTINUATION	-$5,866
														Subtotal = $655,687

Issue Date FY: 2023 ( Subtotal = $672,689 )
2023	2023	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cardiovascular Diseases Research	000	5	6/5/2023	COMPETING CONTINUATION	$672,689
														Subtotal = $672,689

Issue Date FY: 2021 ( Subtotal = $512,408 )
2021	2021	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cardiovascular Diseases Research	000	4	1/19/2021	NON-COMPETING CONTINUATION	$461,166
2021	2021	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cardiovascular Diseases Research	001	4	5/18/2021	NON-COMPETING CONTINUATION	$51,242
														Subtotal = $512,408

Issue Date FY: 2020 ( Subtotal = $517,267 )
2020	2020	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cardiovascular Diseases Research	000	3	2/19/2020	NON-COMPETING CONTINUATION	$517,267
														Subtotal = $517,267

Issue Date FY: 2019 ( Subtotal = $519,825 )
2019	2019	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cardiovascular Diseases Research	000	2	2/2/2019	NON-COMPETING CONTINUATION	$519,825
														Subtotal = $519,825

Issue Date FY: 2018 ( Subtotal = $603,299 )
2018	2018	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cardiovascular Diseases Research	000	1	2/18/2018	NEW	$603,299
														Subtotal = $603,299

Grand Total All Awards = $4,073,744

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Purinergic Regulation of Veinous Endothelial Permeability

Award Number: R01HL137112

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/18/2018

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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