Research descriptions
Lay Description
Each year, more than a million Americans experience a heart attack, which results in damage to their heart muscle. Unfortunately, the heart cannot regenerate or replace the muscle lost after such an event. Our research aims to uncover the factors that inhibit heart muscle growth and use this knowledge to stimulate the creation of new heart muscle cells following a heart attack.
Strong adhesive junctions connect heart muscle cells to their neighbors, enabling them to withstand the constant pumping of blood throughout the body. Cell adhesion proteins on the cell surface form these junctions, anchoring to the cytoskeleton, a network of proteins inside the cell. Currently, our research focuses on linker proteins that connect cell adhesion proteins to the cytoskeleton.
Using an animal model, we have discovered that modifying linker proteins can enhance muscle growth and improve heart function after a heart attack. Our ongoing studies aim to deepen our understanding of how linker proteins regulate heart growth and to apply this knowledge to the development of novel therapies that stimulate the growth of adult heart muscle following a heart attack.
Scientific Description
The Radice Lab seeks to understand the mechanisms underlying the interplay among cellular forces, cell-cell and cell-matrix adhesions, and the cytoskeleton in the developing and adult heart.
More than a million Americans experience a heart attack each year, causing irreversible damage to their heart muscle. Current therapies prolong survival by protecting remaining cardiomyocytes but cannot overcome the fundamental problem of replacing lost cardiomyocytes. Thus, understanding which molecular pathways govern cardiomyocyte proliferation is a high priority in the search for new treatments for heart failure. The transition from hyperplastic to hypertrophic growth in the postnatal heart is accompanied by dynamic remodeling of cell-cell and cell-extracellular matrix (ECM) adhesion structures, suggesting that cell adhesion/cytoskeletal changes play a critical role in myocardial growth control. In support of this idea, our lab found that altering the interaction between N-cadherin and the actin cytoskeleton leads to Yap nuclear accumulation, increased cardiomyocyte proliferation, and improved cardiac function following myocardial infarction in a preclnical situation. Our ongoing studies aim to provide a mechanistic understanding of how mechanotransduction regulates proliferation in the normal heart and apply this knowledge to the design of novel therapies to stimulate adult myocytes to undergo cell division and repair the injured heart.
The remarkable ability of the heart to respond and adapt to increased mechanical load is crucial for maintaining its pumping function in health and disease. Mechanical load is sensed and transduced at the cellular level via a network of load-bearing proteins with distinct mechanical and signaling properties. These characteristics must be coordinated and balanced within cardiomyocytes and across heart tissue to maintain mechanical homeostasis and effective pumping function. How this is accomplished at the molecular, cellular and tissue levels remains unclear. While a variety of proteins are implicated in the mechanosensitivity of adhesion structures, the linker protein vinculin is well-positioned to coordinate mechanical responses as it connects both integrin- and cadherin-based adhesions to the actin cytoskeleton. Using CRISPR/Cas9 gene-editing technology in a preclinical situation, we generated a series of point mutations in vinculin that alter its posttranslational modification (i.e., phosphorylation), thereby enabling investigation of vinculin mechanosensing in disease pathogenesis. The long-term goal of this research is to understand how heart function is robustly maintained in response to varying mechanical demands, how this robustness is perturbed, and how function can be improved after injury (e.g., heart attack).
