About Our Lab
Heart disease is a major health and economic burden worldwide and the leading cause of death in the United States. Although much progress has been made in understanding the causes of ischemic heart disease and heart failure, the molecular underpinnings that contribute to injury have yet to be fully elucidated. Unfortunately, the result is current treatments that are largely ineffective. Our lab aims to better understand the molecular mechanisms responsible for heart injury with the long-term goal of translating these findings to improved therapeutic approaches for patients.
1. Hippo signaling in ischemic heart disease
Mammalian sterile 20-like kinase 1 (Mst1) is a ubiquitously expressed and highly conserved serine/threonine kinase that is activated in the heart during acute myocardial infarction. Mst1 is also the mammalian homolog of Drosophila Hippo, a master regulator of cell growth and death in the fly. Previous work from our group has shown that suppression of Mst1 inhibits injury and prevents cardiac dysfunction after myocardial infarction, suggesting that Mst1 is a promising target of cardiac therapy for ischemic heart disease.
We recently identified Merlin, a scaffold protein and tumor suppressor, as a regulator of Mst1 activation in the stressed heart. Current work is focused on understanding how Merlin is regulated in the heart and how modulation of Merlin activity (i.e. cardiac-specific Merlin knockout mice) affects myocardial infarction.
Schema: Overview of the Hippo signaling pathway
2. Inflammation and heart injury
We are also interested in the role of inflammation and the innate immune response in ischemic heart disease. It is known that a well-orchestrated inflammatory response is necessary to clear debris, activate reparative cells and promote wound healing after injury. However, excessive and/or prolonged inflammation can have deleterious effects and worsen heart function. Therefore, maintaining a balanced inflammatory response is critical to provide maximum cardioprotection. Recently, our work identified cell-type specific functions of RASSF1A in cardiac fibroblasts and cardiomyocytes, leading to distinct cellular outcomes. This led to the discovery of a novel paracrine signaling pathway that can modulate the heart’s response to chronic stress. We are currently extending these studies to investigate the role of RASSF1A in non-cardiac cell types and examining how modulation of RASSF1A activity can influence inflammatory cell activation and the innate immune response, specifically in the stressed heart.
To investigate these hypotheses we utilize systemic and tissue-specific genetically altered mouse models, as well as primary culture of cardiomyocytes, cardiac fibroblasts, cell lines and viral gene transfer.