My laboratory pursues several diverse projects aimed at 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). Similarly, we are investigating the effect of novel paracrine and autocrine secreted factors that program both adaptive and maladaptive signaling effects in striated muscle. A better understanding of signaling effectors that control such processes, coupled with an identification of novel genes, could suggest new treatment strategies for human diseases.
My laboratory is also engaged in understanding the molecular identity of the mesenchymal fibroblast, especially in heart and skeletal muscle, but also in other organs and tissues that are susceptible to fibrotic diseases or wound-healing defects. We have generated a series of genetic tools in the mouse to allow lineage tracing and functional characterization of the parenchymal fibroblast to better understand the function of these cells and how we might control them in disease states or during tissue injury. Fibroblasts undergo phenotypic conversion to a related cell-type known as the myofibroblast (Figure 3), which secretes extracellular matrix and has contractile activity that mediates remodeling of injured areas of tissue. We have identified several novel effectors that regulate how myofibroblasts are formed, along with possible antifibrotic strategies that inhibit these signaling mediators.
We are also interested in understanding how unfolded proteins and the endoplasmic reticulum (ER) stress response affects disease in both heart and skeletal muscle, as well as more broadly in all tissue and cell types. We identified a novel function for the thrombospondin family of presumed extracellular matrix proteins, which in our hands show a prominent function and localization in the ER, where they directly control aspects of the ER stress response to impart cellular protection. Specifically, we showed that upregulation of thrombospondin 4 in heart or skeletal muscle leads to induction of activator transcription factor 6α to produce a protective ER stress response with expansion of the ER compartment, enhanced secretion of extracellular matrix proteins, and greater cycling and replacement of membrane proteins, as well as generally more intracellular vesicles (Figure 4). Induction of thrombospondin 4, which occurs in most injured diseased tissues, has a protective effect by initiating an adaptive ER stress response that reduces unfolded protein accumulation and helps with healing and extracellular matrix integrity.
This research has been supported in part by the National Institutes of Health.
As of February 19, 2016