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Novel peptides for resuscitation

Award Number: R01HL147031
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/15/2019
PERIOD OF PERFORMANCE END DATE: 04/30/2029

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Novel peptides for resuscitation - Cardiac arrest (CA) is a leading cause of death around the globe. In the USA, it affects about 650,000 people annually with an overall survival rate for out-of-hospital cardiac arrest less than 10%. Despite this enormous public health burden, no pharmacological drugs exist to improve CA survival. This proposal is a renewal application of R01HL147031-01 that investigated a novel cell-permeable biological peptide TAT-PHLPP9c to improve CA outcome. This peptide inhibits the phosphatase PHLPP and activates Akt in the heart and brain within minutes after intravenous administration during cardiopulmonary resuscitation (CPR). Remarkable improvement in neurologically intact survival in both mouse and swine CA models was demonstrated, with new biomarkers of metabolic resuscitation identified. However, in addition to metabolic dysfunction, marked intravascular coagulation in the microcirculation of organs after CA also contributes to poor outcomes. This renewal application builds upon new preliminary data showing that in addition to Akt-related metabolic recovery, platelet activation and related thrombo-inflammation via the G Protein α13-Integrin β3 interaction affects CA outcome. Proposed work will examine a novel treatment strategy for CA that combines the use of TAT-PHLPP9c and M3mP6, a lipid-stabilized, high-loading peptide nanoparticle designed to inhibit integrin signaling and platelet activation. Our pilot studies suggest substantial platelet activation and related inflammation within hours after both mouse and swine CA, with only partial attenuation of this thrombo-inflammation by TAT-PHLPP9c. Furthermore, M3mP6, when given during CPR, provides substantial synergistic benefit from TAT-PHLPP9c to 5-day CA survival in a mouse CA model. New aims will use these two complementary novel peptides to examine the synergistic roles of metabolic derangement and thrombo-inflammation in CA survival, and develop a transformative approach to CA with the potential to protect against even prolonged >10-15 min of untreated cardiac arrest. New proposed work will: Aim 1. Examine whether combined treatment of TAT-PHLPP9c and M3mP6 during CPR improves 5-day neurologically intact survival after mouse CA. Aim 2. Study the mechanisms of the synergistic effects of these two peptides in the heart and platelets. Aim 3. Validate the efficacy of TAT-PHLPP9c and M3mP6 in a swine CA model. The concept of administration of novel cell-permeable peptides during CPR to protect against two critical aspects of post-CA syndrome is practical, innovative and highly translational. New mechanistic insights into metabolic injury and thrombo-inflammation and how they interact to affect CA survival would have great potential to develop novel approaches for CA care. Given the magnitude of protection the combined peptides demonstrate in preliminary work, this proposal has potential to transform cardiac arrest care.


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 = $609,362 )
2026	2026	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Cardiovascular Diseases Research	000	6	4/7/2026	NON-COMPETING CONTINUATION	$609,362
														Subtotal = $609,362

Issue Date FY: 2025 ( Subtotal = $644,476 )
2025	2025	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Cardiovascular Diseases Research	000	5	6/1/2025	COMPETING CONTINUATION	$644,476
														Subtotal = $644,476

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Cardiovascular Diseases Research	000	4	7/11/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $695,735 )
2022	2022	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Cardiovascular Diseases Research	001	4	6/17/2022	NON-COMPETING CONTINUATION	$69,575
2022	2022	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Cardiovascular Diseases Research	000	4	3/14/2022	NON-COMPETING CONTINUATION	$626,160
														Subtotal = $695,735

Issue Date FY: 2021 ( Subtotal = $708,527 )
2021	2021	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Cardiovascular Diseases Research	000	3	3/15/2021	NON-COMPETING CONTINUATION	$708,527
														Subtotal = $708,527

Issue Date FY: 2020 ( Subtotal = $738,520 )
2020	2020	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Cardiovascular Diseases Research	000	2	4/10/2020	NON-COMPETING CONTINUATION	$738,520
														Subtotal = $738,520

Issue Date FY: 2019 ( Subtotal = $698,605 )
2019	2019	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Cardiovascular Diseases Research	000	1	4/11/2019	NEW	$698,605
														Subtotal = $698,605

Grand Total All Awards = $4,095,225

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Novel peptides for resuscitation

Award Number: R01HL147031

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/15/2019

PERIOD OF PERFORMANCE END DATE: 04/30/2029

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