My laboratory, which has a number of diverse projects, is fundamentally interested in understanding the molecular mechanisms of heart and skeletal muscle disease. Toward this end, we investigate the basic machinery that underlies cell death, particularly mitochondrial-dependent mechanisms of nonapoptotic death, such as cellular necrosis (Figure 1). Prominent diseases of both heart and skeletal muscle are affected by cellular necrosis. Identifying the genes that control this process should have a substantial impact on human health.
We are also interested in characterizing the intracellular signaling pathways that control cellular growth, differentiation, and replication in cardiac and skeletal muscle. We are dissecting key intracellular signaling pathways, such as calcineurin-NFAT (calcineurin is a calcium-activated phosphatase that signals to nuclear factor of activated T cells, a transcription factor) and MAPK (mitogen-activated protein kinase), as mediators of normal growth and development and disease responsiveness (Figure 2). A better understanding of signaling pathways that control such processes, coupled with an identification of novel genes, could suggest new treatment strategies for human diseases.
To suggest additional targets for treating human disease, we are also examining the transcriptional regulatory factors and epigenetic mechanisms that regulate cardiac and skeletal muscle differentiation, growth, death, and replication. We have a long-standing interest in characterizing the function of the zinc finger–containing transcription factors GATA4, -5, and -6 as regulators of cardiac development and adult heart disease (Figure 3). These same factors appear to play additional roles in the regulation of endoderm function and even angiogenesis. We continue to explore both genetic and epigenetic vantage points to characterize the function of these transcription factors.
My laboratory is also engaged in identifying novel secreted protein factors (e.g., cytokines, growth factors, chemokines) from the heart that might control disease responsiveness (Figure 4). We have identified a number of secreted factors that control disease responsiveness of the heart, such as the extracellular matrix protein periostin or the transforming growth factor β (TGFβ) superfamily member GDF-15 (growth and differentiation factor-15). We have also uncovered a number of novel factors made by the myocardium and secreted in endocrine, paracrine, and autocrine regulatory capacities. These factors may shed light on the mechanisms whereby the myocardium is affected by disease stimulus and is even an endocrine effector of other tissues.
We are also studying the fibroblast and how it functions during disease to alter the extracellular matrix, which has an impact on organ and tissue remodeling. Our investigations have suggested that fibroblasts are important regulators of disease responsiveness, through novel regulatory factors that we are still investigating.
Finally, to further explore the paradigms of excitation-transcription coupling and excitation-signaling coupling, we are investigating the basic mechanisms of intracellular calcium handling in cardiac and skeletal muscle (Figure 5). We have shown that disease in muscular dystrophy is associated with altered intracellular calcium handling that directly affects mitochondria, resulting in necrotic cell death. We are attempting to determine how calcium is altered in skeletal muscle from dystrophic animal models and whether we can genetically complement any identified defect in calcium handling to mitigate disease. Transgenic and gene-targeted mice have been generated with altered membrane and sarcoplasmic reticulum (SR) calcium handling. We have been using a similar strategy in the heart to determine how TRPC channels (transient receptor potential canonical subclass [cationic channels]), L-type calcium channels, T-type calcium channels, IP3 receptors, and SR calcium handling alter disease responsiveness of the heart.
