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Protective role of Endothelial Receptor Interacting Protein Kinase 3 (RIPK3) in acute lung injury

Award Number: K08HL166958
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 02/01/2024
PERIOD OF PERFORMANCE END DATE: 01/31/2029

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Protective role of Endothelial Receptor Interacting Protein Kinase 3 (RIPK3) in acute lung injury - PROJECT SUMMARY/ABSTRACT This proposal is for a five-year research career development program, focused on understanding how “neutropenic inflammation” activates the endothelium toward programmed cell death and the protective role of necrotic cell death protein receptor interacting protein kinase-3 (RIPK3) in this inflammatory environment. The candidate has been appointed Assistant Professor in the Department of Medicine at Weill Cornell Medicine. This proposal is a natural extension of the candidate's previous research in high vascular injury ARDS populations (Price DR, AJRCCM, 2021; ICM, 2021) and vascular cell death work in ARDS (Price DR, Am J Patho, 2023). It outlines a plan for the candidate to achieve his goal of becoming an expert in vascular biology and acute lung injury, extending the training of the candidate as identified here and reflected in the mentorship of Dr. Augustine Choi and Dr. Shahin Rafii: 1. Define the role of neutropenic inflammation in mouse lung injury and human organoid models, and 2. Determine a functional role for RIPK3 in inflammatory acute lung injury, and 3. Define important necrotic cell death and vascular injury biomarkers in inflammatory ARDS. The proposed experiments and the exciting training plan will impart the candidate with a unique combination of skills that will position him to transition into a successful independent physician scientist studying vascular injury in ARDS. The acute respiratory distress syndrome (ARDS) is a common, often fatal, inflammatory lung injury for which there are limited therapeutic options. The role of vascular injury as a disease-modifying factor in ARDS pathogenesis has been well established. In contrast, the functional significance of an aberrantly injured vascular cell upregulating necrotic cell death proteins, including receptor interacting protein kinase 3 (RIPK3), remains largely unexplored in ARDS investigations, representing a potential target for future ARDS therapeutics. In this proposal, I leverage my recent work highlighting neutropenic ARDS as a high endothelial stress population to propose studies that test how excessive “neutropenic inflammation” activates the endothelium toward programmed cell death and the protective role of endothelial RIPK3 in this inflammatory environment. To do this, I have developed a neutropenic lung injury model that activates the lung endothelium and promotes RIPK3 expression. In Aim1, we will define the role of neutropenic inflammation in mouse lung injury and human organoid models. In Aim 2, we will determine a functional role for endothelial RIPK3 in acute lung injury using gene targeted mice, specifically the endothelial cell-specific deletion of RIPK3 mice. And in Aim 3, we will characterize dysregulated cell death and vascular permeability pathways in inflammatory ARDS by correlate circulating necroptosis and vascular permeability proteins with mortality and clinical indices of acute lung injury. Collectively, these studies will provide novel insight into pathways of neutropenic inflammation and endothelial RIPK3 in regulating vascular injury in ARDS.


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: 2026 ( Subtotal = $169,020 )
2026	2026	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Lung Diseases Research	000	3	3/19/2026	NON-COMPETING CONTINUATION	$169,020
														Subtotal = $169,020

Issue Date FY: 2025 ( Subtotal = $169,020 )
2025	2025	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Lung Diseases Research	000	2	1/9/2025	NON-COMPETING CONTINUATION	$169,020
														Subtotal = $169,020

Issue Date FY: 2024 ( Subtotal = $169,020 )
2024	2024	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Lung Diseases Research	001	1	9/12/2024	NEW	$0
2024	2024	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Lung Diseases Research	000	1	1/30/2024	NEW	$169,020
														Subtotal = $169,020

Grand Total All Awards = $507,060

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Protective role of Endothelial Receptor Interacting Protein Kinase 3 (RIPK3) in acute lung injury

Award Number: K08HL166958

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 02/01/2024

PERIOD OF PERFORMANCE END DATE: 01/31/2029

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