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IL-1R1 in Endothelial-to-Mesenchymal Activation

Award Number: R01HL172846
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2024
PERIOD OF PERFORMANCE END DATE: 01/31/2029

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IL-1R1 in Endothelial-to-Mesenchymal Activation - PROJECT SUMMARY: Endothelial-to-mesenchymal transition (EndMT) has been detected in atherosclerosis, and the extent of EndMT observed in the human plaques strongly correlates with the severity of the disease, implying clinical relevance of EndMT in the pathogenesis of atherosclerosis. Both disturbed blood flow (d-flow) and interleukin-1 signaling (IL-1) have been implicated in EndMT formation. The signaling pathway that links d-flow and EndMT is still unclear. Moreover, IL-1 as a therapeutic target has already been tested and the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) assessed the therapeutic effect of the anti-IL-1β antibody in patients after myocardial infarction and showed 31% reduction of cardiovascular and all-cause mortality. However, some of those patients developed immunosuppressive off-target effects. In addition, there is no clear principal cell type in human severe atherosclerosis responsible for IL-1 signaling. Our recently published work has demonstrated that d-flow induces activation of interleukin-1 receptor signaling kinase (IRAK1) within endothelial cells (ECs), with an increase in p-IRAK1 levels in human and mouse atherosclerosis. IRAK1 is co-expressed with EndMT in severe atherosclerosis, and deletion of IRAK1 decreases EndMT in vitro, identifying a novel role for IRAK1 as a downstream effector in d-flow-induced EndMT. Our central hypothesis is that IRAK1 activation mediates d- flow-induced EndMT and selective inhibition of IRAK1 will allow efficient inhibition of atherosclerosis without promoting significant immunosuppression. Aim 1 Determine the mechanistic role of IRAK1 activation in oscillatory flow-induced EndMT. Our preliminary data supports IRAK1 activation by d-flow and that mediates EndMT formation. Aim 1.1, utilizing CRISPR Cas-9 KO selective deletion and re-expressing vectors, we will test the role of IRAK1 in oscillatory flow-induced EndMT. In Aim 1.2, we will evaluate the activating roles of IRAK1 domains by transiently transfecting IRAK1 truncated mutants into IRAK1-depleted and overexpressed ECs and we will measure Phospho-IRAK1 and EndMT after oscillatory flow. In Aim 1.3, we will assess the functional role of IRAK1 endogenous interactions by utilizing immunoprecipitations, gene silencing, and mass spectrometry. Aim 2 will determine if selective inhibition of IRAK1 in d-flow-induced EndMT prevents atherosclerosis progression. We will use Cre-lox endothelial-specific lineage tracing and novel endothelial-specific IRAK1 knockout mice and IRAK1 selective inhibitor to provide the first assessment of IRAK1 inhibition on EndMT formation in vivo. Fibrous cap thickness, plaque lesion size, composition, and EndMT will be assessed in both partial carotid ligation model of d-flow (Aim2.1) and diet-induced atherosclerosis (Aim2.2). FACS analysis of blood and plaques will be done to assess total and differential leukocytes and proinflammatory cytokines. These studies will determine the dynamic interplay between disturbed flow and IL-1 signaling in EndMT and will define a novel role for IRAK1 as a novel therapeutic target in d-flow-induced EndMT and atherosclerosis.


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 = $410,370 )
2025	2025	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Cardiovascular Diseases Research	001	2	1/27/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$410,370
2025	2025	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	4215 EMILE ST	OMAHA	NE	68105	DOUGLAS	USA	Cardiovascular Diseases Research	003	2	5/22/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$300,596
2025	2024	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Cardiovascular Diseases Research	000	1	1/26/2025	NEW	$0
2025	2024	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Cardiovascular Diseases Research	002	1	5/22/2025	NEW	-$300,596
														Subtotal = $410,370

Issue Date FY: 2024 ( Subtotal = $433,689 )
2024	2024	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Cardiovascular Diseases Research	001	1	5/30/2024	NEW	$43,370
2024	2024	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Cardiovascular Diseases Research	000	1	2/28/2024	NEW	$390,319
														Subtotal = $433,689

Grand Total All Awards = $844,059

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IL-1R1 in Endothelial-to-Mesenchymal Activation

Award Number: R01HL172846

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2024

PERIOD OF PERFORMANCE END DATE: 01/31/2029

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