# Novel Therapies for CPR

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2020 · $306,751

## Abstract

Approximately 600,000 people in the United States experience sudden cardiac arrest (SCA) each year.
SCA is the third leading cause of U.S. deaths. Active cooling after the start of cardiopulmonary resuscitation
(CPR) can increase both heart and brain functional recovery with improved long-term survival. However, such
cooling can be difficult to timely implement during CPR and when delayed may benefit only a subset of SCA
patients. Unfortunately, no medications exist that improve long-term cardiac arrest survival. Proposed work
develops first-of-their class biologic resuscitation agents that reproduce critical mechanisms of active cooling
protection within minutes of intravenous delivery during CPR.
 The central hypothesis of this proposal is that rapid, specific and transient PTEN inhibition with onset of
action within minutes of CPR and maintained for hours after CPR is highly protective of cardiac arrest survival.
The cell permeable peptide TAT-PTEN9c reverses contractile failure (i.e. stunning) by enhancing glycolysis and
activating pyruvate dehydrogenase (PDH). This enhanced glucose utilization decreases glucose diversion to
sorbitol and attenuates additional cardiac injury related to sorbitol induced osmotic stress and compensatory
taurine release. Nicotinamide (NAM, i.e. vitamin B3), a precursor of myocardial NAD+, is proposed to be a highly
synergistic adjunct to TAT-PTEN9c for both NAD+-driven glucose utilization and NAD+-driven clearance of high
myocardial sorbitol concentrations. The resulting improvement of cardiac function within hours after CPR
supports increased tissue perfusion critical for 3-day neurologically intact survival. Three complementary aims
using heart cell and isolated heart models of stunning, and determination of outcomes common to both mouse
and human cardiac arrest, support the success of proposed work.
Aim 1. Examine the efficacy of a novel TAT-fused peptide used in Aims #2 and #3 that specifically and rapidly
blocks endogenous PTEN activity and reverses ischemic stunning in mouse cardiomyocytes. TAT-PTEN9c is a
20- amino acid cell-permeable peptide in which the TAT protein transduction domain is linked to the PTEN C-
terminal 9 amino acids. Outcomes measured include return of contractility, protein kinase B (Akt) and GSK3β
phosphorylation, and NAD+/NADH ratios and ATP contents.
Aim 2. Determine the effect of TAT-PTEN9c and NAM supplementation on myocardial glucose and fat
metabolism, pH, energetic recovery and cardiac function in the intact functioning rat heart model of global I/R.
NMR-measured metabolic outcomes of glucose utilization (i.e. glycolysis and oxidation, versus diversion to
sorbitol) will be linked to fat metabolism, improved contractile recovery and increased cardiac taurine
preservation.
Aim 3. Determine whether TAT-PTEN9C or NAM, given alone and in combination after CPR, significantly
improves immediate cardiac recovery as well as 72 h neurologically intact survival using an established in vivo
m...

## Key facts

- **NIH application ID:** 9897537
- **Project number:** 5R01GM120485-04
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** J. MICHAEL O'DONNELL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $306,751
- **Award type:** 5
- **Project period:** 2017-07-15 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9897537

## Citation

> US National Institutes of Health, RePORTER application 9897537, Novel Therapies for CPR (5R01GM120485-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9897537. Licensed CC0.

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