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The role of neutrophil YAP in cardiac ischemia/reperfusion inflammation and injury

Award Number: F31HL162545
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 01/01/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2024

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The role of neutrophil YAP in cardiac ischemia/reperfusion inflammation and injury - Title: The role of neutrophil YAP in cardiac ischemia/reperfusion inflammation and injury Student: Jamie Francisco, M.S. Mentor: Dr. Dominic Del Re, PhD. Abstract: Myocardial Infarction (MI) is the number one cause of death worldwide, claiming more lives than the three most prevalent cancers combined. While reperfusion is currently the gold standard treatment of ischemic injury in the heart, it paradoxically worsens cardiac outcomes by increasing inflammation and apoptosis, furthering myocyte loss and expanding the infarct. Despite being a major contributor to worsening cardiac outcomes, there are no available treatments for this secondary injury caused by reperfusion, presenting a major limitation in the treatment of MI. Neutrophils are among the first inflammatory cells recruited to the heart after injury and their numbers have been shown to positively correlate to infarct size. Although neutrophils contribute to acute inflammation and infarct expansion, neutrophil depletion results in defective cardiac repair after infarct. Therefore, further investigation into the mechanisms of specific neutrophil functions is needed to regulate inflammation and improve cardiac outcomes during reperfusion. The long-term goal of this research is to uncover novel therapeutic targets of proinflammatory neutrophil functions to make possible targeted modulation of inflammation without affecting repair during reperfusion. Previous investigations by our lab and others have identified Yes-Associated Protein (YAP), a downstream effector of the Hippo pathway, as a critical regulator of cardiac outcomes after ischemic heart injury. Preliminary data from our newly generated neutrophil-specific YAP KO mouse (YAP F//F: MRP8-cre) show decreased infarct size and inflammatory gene expression when compared to controls after acute ischemia/reperfusion (I/R). These data support our hypothesis that neutrophil YAP positively regulates inflammation and therefore, cardiac injury, after I/R. The goal of the proposed study is to define the role of YAP in specific pro-inflammatory neutrophil functions and the subsequent effect on cardiac injury during reperfusion to improve cardiac outcomes after I/R injury. To investigate this, we propose the following aims: 1) Determine cardiac injury and post infarct inflammatory status in neutrophil-specific YAP KO mice, 2) Determine the effect of YAP expression on neutrophil function during reperfusion and investigate the underlying mechanism. Upon completion, we will have elucidated the role of YAP in specific neutrophil proinflammatory functions during cardiac reperfusion. Furthermore, we believe these studies will reveal novel therapeutic targets for the modulation of inflammation without affecting the repair mechanism in the heart. As the injury due to reperfusion currently has no effective treatment, the results of this work could advance the field toward improved therapeutic options for MI patients.


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 = -$246 )
2025	2022	RUTGERS, THE STATE UNIVERSITY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	000	1	1/23/2025	NEW	-$246
														Subtotal = -$246

Issue Date FY: 2024 ( Subtotal = $43,428 )
2024	2024	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Cardiovascular Diseases Research	001	3	8/29/2024	NON-COMPETING CONTINUATION	$1,280
2024	2024	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Cardiovascular Diseases Research	000	3	11/17/2023	NON-COMPETING CONTINUATION	$42,148
														Subtotal = $43,428

Issue Date FY: 2023 ( Subtotal = $41,206 )
2023	2023	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Cardiovascular Diseases Research	000	2	11/29/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$41,206
														Subtotal = $41,206

Issue Date FY: 2022 ( Subtotal = $41,206 )
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	002	1	6/24/2022	NEW	$716
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	000	1	12/9/2021	NEW	$40,490
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	001	1	12/9/2021	NEW	$0
														Subtotal = $41,206

Grand Total All Awards = $125,594

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The role of neutrophil YAP in cardiac ischemia/reperfusion inflammation and injury

Award Number: F31HL162545

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 01/01/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2024

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