Endothelial dysfunction in the development of aortic degeneration, dissection, and rupture

Ended Project Grant Awarded Last action

Award ID
R01HL159988
Recipient
Awarding agency
Obligated
$4,523,321

Award facts

Assistance listing
93.837 Cardiovascular Diseases Research
Completion date
Place of performance
Houston, TX 77030, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Ascending thoracic aortic aneurysms and dissections (ATAAD) are extremely lethal diseases. The contribution of endothelial dysfunction in ATAAD has received limited attention and thus remains poorly understood. COM- pelling evidence from our preliminary studies suggests a critical role for endothelial cell (EC) injury and endo- thelial hyperpermeability in aortic degeneration and ATAAD development. [scrna-SEQ analysis of aortas from sporadic ATAAD patients revealed significant EC dysfunction with upregulation of RIP3 and gsdmd that trig- GER necroptosis and pyroptosis, respectively. In a sporadic ATAAD mouse model, aortic challenge with high- FAT diet and angiotensin II infusion induced RIP3 and gsdmd in ECS, caused endothelial hyperpermeability, nanoparticle infiltration, interlaminar space expansion, elastic fiber delamination, and microdissection. EC-RIP3- /- or EC-gsdmd-/- showed markedly reduced nanoparticle infiltration and aortic degeneration.] further investiga- tion with scatac-SEQ showed that aortic challenge increased chromatin accessibility at promoters/enhancers of the pro-inflammatory/pro-death genes, likely by activating pro-inflammatory transcription factors (TFS) such as IRF3. In human ECS, cytosolic DNA and sting-TBK1 signaling was a potent upstream trigger for the acti- vation of IRF3 and BRG1 and induction of gsdmd expression. The objective of this application is to test the central hypothesis that aortic stress activates inflammatory signaling within ECS that triggers epigenetic in- duction of a pro-inflammatory and pro-death program, leading to EC necroptosis/pyroptosis, barrier dysfunc- tion, blood component infiltration, aortic wall degeneration, and ATAAD formation. [aim 1 will test the hypothe- SIS that RIP3-mediated EC necroptosis and gsdmd-mediated EC pyroptosis compromise EC barrier function, thereby facilitating the infiltration of inflammatory blood components and promoting aortic degeneration and ATAAD formation. In our sporadic ATAAD model, we will compare aortic degeneration and ATAAD formation in control mice, EC-RIP3-/- mice, EC-gsdmd-/- mice, and WT mice treated with a necroptosis/pyroptosis inhibi- TOR.] aim 2 will test the hypothesis that aortic stress activates inflammatory signaling (e.g., sting pathway) within ECS that triggers epigenetic induction of a pro-inflammatory and pro-death program. We will perform scrna-SEQ and scatac-SEQ analyses of ECS in aortas from unchallenged and challenged WT mice and EC- specific sting KO mice. Aim 3 will test the hypothesis that stress signals (e.g., cytosolic DNA) trigger sensing- signaling pathways (e.g., sting-TBK) that directly activates chromatin remodeling complexes (e.g., BRG1/SWI/SNF) and TFS (e.g., IRF3) that induce gsdmd expression and promote EC pyroptosis. We will test the hypothesis in cultured human ECS (aim 3A) and [confirm the mechanistic links in human ATAAD aortas (aim 3B)]. We expect that the proposed studies will provide novel insight into the molecular mechanisms of sporadic aortic degeneration and ATAAD formation, which will in turn enable development of new treatments for preventing disease progression and its fatal sequelae. 1

Transactions

Action Obligated Date
Amendment $633,427
Amendment $620,759
Amendment $620,759
Amendment $662,094
Amendment $662,094
Amendment $662,094
Original award $662,094

Subawards

Subrecipient Amount Awarded
Geisinger Clinic Agreement: $43,578 Amd 1: $60,509 Amd 2: $61,766 The overall objectives of this application are to understand the mechanisms underlying epigenetic induction… $165,853
Universitätsklinikum Essen (Anstalt DES Öffentlichen Rechts) Agreement: $90,523 Amd 1: $0 Amd 2: $90,523 Dr. Dobrev will oversee the experiments conducted at Universitätsklinikum Essen and coordinate with Dr. Na Li… $181,046
Regents Of The University Of Minnesota Agreement: $75,899 Scope Using a well-established mouse model for sickle cell anemia, caspase-deficient mice, and bone marrow transplants, we will explore how… $75,899

Quick answers

Who received award R01HL159988?

R01HL159988 was awarded to Baylor College Of Medicine by National Heart Lung and Blood Institute (National Institutes of Health) on July 15, 2022.

How much is award R01HL159988 worth?

$4,523,321 has been obligated on R01HL159988.

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