P01HL160476

Mechanisms That Govern Cardiomyocyte Proliferation and Remuscularization Following Ventricular Injury - Abstract

Mechanisms That Govern Cardiomyocyte Proliferation and Remuscularization Following Ventricular Injury Program Overall

The overall goal for the treatment of myocardial infarction is to replace the scar tissue caused by ischemic injury with functional cardiac muscle. Since adult mammalian cardiomyocytes (CMs) are non-proliferative, and the engraftment rate for cardiac cell therapy is extremely low, most of the remuscularizing initiatives following infarction have been unsuccessful.

However, recent preliminary studies from our laboratories using neonatal pigs have shown that when myocardial infarction (MI) is induced on postnatal day 1 (P1), CMs re-enter the cell cycle, proliferate, and completely restore cardiac function with little scarring. Furthermore, we have found that these neonatal hearts with the P1 injury have a very active and prolonged CM proliferative machinery. Consequently, a second LAD ligation injury at P28, which resulted in a large infarct (TTC) at day 2-7 post LAD ligation, produced no visible infarct 4 weeks following injury. This was a remarkable result as it demonstrated, for the first time, that a heart of a large mammal could remuscularize infarcted heart tissue by CM proliferation.

The studies comprising this Program Project Grant (PPG) application will examine mechanisms whereby CMs reenter the cell cycle and new strategies to remuscularize injured hearts.

Project 1 will identify the CM cell-cycle regulators that are activated by MI in one-day-old pigs and construct human cardiac muscle patches (HCMP) of unprecedented clinically relevant dimensions from layers of proliferating hiPSC-CMs with activated cell cycle regulators and other cardiac cells. Subsequent experiments will determine whether the identified factors and HCMPs can remuscularize the hearts of adult pigs after MI.

Project 2 will use genetic strategies, viral vectors, and modified RNAs to investigate whether members of the Sonic Hedgehog signaling pathway, including GLI1 and SOX4, which have already been shown to induce proliferation in cultured CMs, will promote CM proliferation in the injured hearts of adult mice and pigs. In addition, studies will examine the capacity of the master regulator, ETV2, to promote neovascularization and promote repair of the injured hearts of adult mice and pigs.

Project 3 will be an extension of previous observations that mammalian cell-cycle arrest is at least partially induced by the increase in oxygen metabolism that occurs after birth, and that severe systemic hypoxia upregulates proline metabolism and induces CM proliferation in adult mice. The proposed studies will examine whether proline metabolism regulates CM survival and proliferation during chronic hypoxia.

Collectively, these three projects, the associated cores, and the expertise of the investigators will accelerate and amplify the studies to address the central objective of this P01 proposal: to remuscularize the injured ventricle from "within," by promoting endogenous CM proliferation, and from "outside," by transplanting functionally mature HCMPs that are primed for in-vivo CM proliferation.

University Of Alabama At Birmingham

TO FOSTER HEART AND VASCULAR RESEARCH IN THE BASIC, TRANSLATIONAL, CLINICAL AND POPULATION SCIENCES, AND TO FOSTER TRAINING TO BUILD TALENTED YOUNG INVESTIGATORS IN THESE AREAS, FUNDED THROUGH COMPETITIVE RESEARCH TRAINING GRANTS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

Birmingham, Alabama 352940004 United States

Single Zip Code

NHLBI Program Project Applications (P01 Clinical Trials Optional) (PAR-21-088)

Amendment Since initial award the total obligations have increased 280% from $2,387,932 to $9,063,431.