Mechanistic clinical trial of ?-blocker administration for reactivating cardiomyocyte division in tetralogy of fallot
Active Project Grant Awarded Last action
- Award ID
- R01HL155597
- Recipient
-
Weill Medical College Of Cornell University UEI YNT8TCJH8FQ8
- Awarding agency
-
National Heart Lung and Blood Institute
National Institutes of Health, Department of Health and Human Services
- Obligated
- $12,062,999
Award facts
- Assistance listing
- 93.837 Cardiovascular Diseases Research
- Completion date 91% complete
- Originally
- Funding
-
- $11,363,428.00 Federal
- $699,571.00 Non-federal
- Place of performance
- New York, NY 10065, USA
Award details come from USAspending.gov.
Description
- Abstract
- Right ventricular remodeling leads to serious complications in congenital heart disease. Congenital heart disease (CHD) is the most common birth defect. Due to improved diagnostics and surgery, 1 million patients live in the US with CHD, many of whom develop right ventricular (RV) heart failure. Our understanding of the underlying pathobiology and therapies are very limited, creating a pressing research need. Patients with tetralogy of fallot with pulmonary stenosis (TOF/PS), the most common form of cyanotic CHD and the form most available for research, develop adverse RV remodeling, leading to heart failure and arrhythmias. IT has been thought that the RV remodeling is a consequence of surgical repair. However, we have recently shown that TOF/PS patients have decreased heart muscle cell (cardiomyocyte) division, indicating the possibility of developing a new mechanistic paradigm of RV heart failure development in CHD. Increased SS-adrenergic receptor signaling decreases cardiomyocyte proliferation in TOF/PS. We have taken an innovative research approach, using administration of thymidine labeled with a stable isotope tag (15N-thymidine). Proliferating cells incorporate 15N-thymidine into their DNA, which we visualize with multi- isotope imaging mass spectrometry (mims) analysis of pieces of RV myocardium. By detecting cardiomyocytes labeled with 15N-thymidine, mims revealed decreased cardiomyocyte division in TOF/PS. Our mechanistic investigations showed that overactive SS-adrenergic receptor signaling inhibits cardiomyocyte division. Our pre-clinical studies in neonatal mice and cardiomyocytes from TOF/PS infants demonstrate that administration of the SS-adrenergic receptor blocker propranolol increases cardiomyocyte division. SS-blockers have been used in TOF/PS, but this use has been limited to preventing hypercyanotic spells. We propose a randomized, placebo-controlled (1:1), double-blinded, single-center clinical trial of 40 TOF/PS infants to test the mechanistic hypothesis that SS-blocker administration in TOF/PS infants increases cardiomyocyte division and decreases RV hypertrophy. The recent success of propranolol administration in infantile hemangiomas and american academy of pediatrics guidelines provide the necessary pharmacokinetics and safety experience to support these studies in infants. As primary outcome, we will quantify cardiomyocyte division using our innovative 15N-thymidine labeling approach with mims readout. As a secondary outcome, we will characterize changes in RV and cardiomyocyte hypertrophy. This initial single-center trial will provide the foundation for future multi-center randomized controlled trials of propranolol administration in infants with TOF/PS and other types of CHD at risk for RV remodeling, such as hypoplastic left heart syndrome, with the long-term goal of preventing RV failure. The heart institute at children's hospital of pittsburgh is ideal for this research. We have achieved the lowest mortality of infant cardiac surgery and have the research infrastructure to carry out the proposed work.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $0 | |
| Amendment | $0 | |
| Amendment | $0 | |
| Amendment | $0 | |
| Amendment | $0 | |
| Amendment | $0 | |
| Amendment | $55,210 | |
| Amendment | $55,210 | |
| Amendment | $55,210 | |
| Amendment | $55,210 | |
| Amendment | $496,892 | |
| Amendment | $496,892 | |
| Amendment | $496,892 | |
| Amendment | $496,892 | |
| Amendment | -$694,289 | |
| Amendment | -$22,331 | |
| Amendment | -$77,541 | |
| Amendment | -$77,541 | |
| Amendment | $1,001,351 | |
| Amendment | -$22,331 | |
| Amendment | -$694,289 | |
| Amendment | $0 | |
| Amendment | $1,001,351 | |
| Amendment | -$229,521 | |
| Amendment | $0 | |
| Amendment | -$694,289 | |
| Amendment | $1,001,351 | |
| Amendment | -$229,521 | |
| Amendment | -$229,521 | |
| Amendment | $48,293 | |
| Amendment | $48,293 | |
| Amendment | $48,293 | |
| Amendment | $48,293 | |
| Amendment | $89,713 | |
| Amendment | $89,713 | |
| Amendment | $89,713 | |
| Amendment | $89,713 | |
| Amendment | $89,713 | |
| Amendment | $543,291 | |
| Amendment | $0 | |
| Amendment | $543,291 | |
| Amendment | $0 | |
| Amendment | $543,291 | |
| Amendment | $0 | |
| Amendment | $543,291 | |
| Amendment | $0 | |
| Amendment | $0 | |
| Amendment | $543,291 | |
| Amendment | $0 | |
| Amendment | $0 |
Show 40 more
Latest 50 listed here. See the rest on GovTribe.
Subawards
| Subrecipient | Amount | Awarded |
|---|---|---|
| University Of Pittsburgh - Of The Commonwealth System Of Higher Education | $514,825 | |
| Subrecipient not on record | $164,490 | |
| New England Research Institutes Inc. | $74,577 | |
| New England Research Institutes Inc. | $249,551 |
Quick answers
Who received award R01HL155597?
R01HL155597 was awarded to Weill Medical College Of Cornell University by National Heart Lung and Blood Institute (National Institutes of Health) on July 1, 2021.
How much is award R01HL155597 worth?
$12,062,999 has been obligated on R01HL155597: $11,363,428 in federal funding and $699,571 in non-federal funding.
On GovTribe
See this award's full record
- Every transaction and subaward
- The recipient's other awards and teaming partners
- Similar grant awards
- Ask GovTribe AI about this award