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Supraphysiologic Shear Stresses Associated with Cardiopulmonary Bypass are Sufficient to Activate RIKP3 Signaling

Award Number: R01HD106628
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/11/2022
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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Supraphysiologic Shear Stresses Associated with Cardiopulmonary Bypass are Sufficient to Activate RIKP3 Signaling - The vast majority of pediatric open-heart surgeries require the patient to be supported by cardiopulmonary bypass (CPB). Exposure to CPB causes systemic inflammation and resultant multi-organ dysfunction. Post-CPB inflammation is believed to be caused by exposure of the patient’s blood cells to the plastic tubing of the CPB circuit and unphysiological high shear stress. However, the mechanisms underlying this process are unclear. Our long-term goal is to understand how these insults contribute to post-CPB inflammation and translate this knowledge into novel treatment strategies. The scientific premise for this project is that Receptor-Interacting serine/threonine-Protein Kinase 3 (RIPK3) signaling is a novel mediator of CPB associated inflammation that can be targeted to improve outcomes for neonatal cardiac surgery patients. Data from neonatal CBP patients, a large animal model of CPB, and in vitro experiments form the basis of our scientific premise. We recently published that RIPK3 and necroptosis play a role in post-CPB inflammation. Our data demonstrate that RIPK3 plays a role in post-CPB inflammation. We established that supraphysiologic shear stresses present during CPB are sufficient to activate RIPK3 signaling in vitro and in a piglet model of CPB. Mechanistically, we found that shear stress-initiated calcium signaling pathways are critical to the activation of monocytic cells. We have identified specific pathways that can be targeted with small molecules to reduce CPB-activation of RIPK3 with goal of reducing systemic inflammatory response and organ dysfunction. We hypothesize that CPB-associated shear stress activates RIPK3 mediated inflammation. The objectives of this proposal are 1) to determine how CPB activates RIPK3 signaling, 2) elucidate how RIPK3 signaling contributes to CPB-associated inflammation/organ dysfunction, and 3) determine if blocking RIPK3 signaling is sufficient to reduce CPB- associated inflammation and organ dysfunction. Our approach will consist of two specific aims: Aim 1. Determine how shear stress activates RIPK3 signaling in circulating myeloid cells. We postulate that supraphysiologic shear stress is sufficient to activate RIPK3 signaling. We will characterize the shear stress thresholds and molecular mechanism responsible for RIPK3 activation during CPB with a focus on the roles that the cell cortex, calcium signaling cascade, and shear responsive kinases play in this response. Aim 2. Demonstrate that RIPK3 signaling mediates CPB-associated inflammation and organ dysfunction. We postulate that RIPK3 signaling is required for the inflammatory response to CPB. RIPK3 can help propagate inflammation via necroptosis, the release of cytokines, and leukocyte migration. We will perform in vitro and in vivo experiments to demonstrate that targeting RIPK3 signaling reduces CPB-associated inflammation. This research is novel and significant – elucidating how CPB activates RIPK3 signaling and necroptosis could enable a new treatment paradigm for CPB patients, improve outcomes, and reduce healthcare costs, since the proposed signaling pathways can be targeted by small molecules in clinical use or pre-clinical development.


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 = $725,965 )
2026	2026	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Child Health and Human Development Extramural Research	000	5	3/3/2026	NON-COMPETING CONTINUATION	$725,965
														Subtotal = $725,965

Issue Date FY: 2025 ( Subtotal = $770,727 )
2025	2025	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Child Health and Human Development Extramural Research	000	4	2/18/2025	NON-COMPETING CONTINUATION	$693,654
2025	2025	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Child Health and Human Development Extramural Research	001	4	4/16/2025	NON-COMPETING CONTINUATION	$77,073
														Subtotal = $770,727

Issue Date FY: 2024 ( Subtotal = $788,165 )
2024	2024	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Child Health and Human Development Extramural Research	001	3	5/2/2024	NON-COMPETING CONTINUATION	$71,651
2024	2024	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Child Health and Human Development Extramural Research	000	3	2/14/2024	NON-COMPETING CONTINUATION	$716,514
														Subtotal = $788,165

Issue Date FY: 2023 ( Subtotal = $801,557 )
2023	2023	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Child Health and Human Development Extramural Research	000	2	2/23/2023	NON-COMPETING CONTINUATION	$801,557
														Subtotal = $801,557

Issue Date FY: 2022 ( Subtotal = $829,782 )
2022	2022	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Child Health and Human Development Extramural Research	000	1	4/8/2022	NEW	$829,782
														Subtotal = $829,782

Grand Total All Awards = $3,916,196

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Supraphysiologic Shear Stresses Associated with Cardiopulmonary Bypass are Sufficient to Activate RIKP3 Signaling

Award Number: R01HD106628

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/11/2022

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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