Research in the Small Lab is focused on understanding the molecular mechanisms that govern how a cell responds to its surroundings during development or following tissue injury. Specifically, we are interested in defining the gene regulatory circuits that are activated following cardiac injury, and how these circuits define a cellular response. To this end, we have three main projects based on gene regulation studies during tissue injury or remodeling:
1. One major component of wound healing, in dermal wounds or a damaged organ alike, is the proliferation and activation of fibroblasts, called "myofibroblasts". Activated myofibroblasts are contractile cells that promote wound closure due in part to the expression of smooth muscle contractile proteins and the deposition of high levels of extracellular matrix. My lab is dedicated to identifying the cellular source of these contractile fibroblasts in the heart and understanding the factors involved in their differentiation following injury.
2. Myocardin-related transcription factor (MRTF)-A is a ubiquitously expressed signal responsive transcriptional co-factor for serum response factor (SRF) that moves to the nucleus in response to various cues that promote F-actin polymerization. I have recently discovered an important role of MRTF-A during myofibroblast differentiation and scar formation following myocardial infarction. My lab is currently studying the mechanisms controlling MRTF activation during development or following cardiac injury, and identifying novel partners in these processes. MRTFs and myofibroblast differentiation are also intriguing therapeutic targets for the prevention or treatment of diseases characterized by inappropriate contractility or scar formation. Therefore, in an extension of this project, we are pursuing novel small molecule modifiers of MRTF activity and myofibroblast differentiation using cell biology and mouse models of wound healing.
3. I have recently identified a number of microRNAs that are activated by SRF and MRTF-A, some of which play a role in cardiovascular remodeling. We are interested in defining the importance of post-transcriptional regulation of gene expression by these microRNAs in tissue homeostasis. The main goal of this aim would be to discover novel cooperative interactions between seemingly unrelated microRNAs via regulation of common mRNAs or physiological pathways.
These projects utilize experimental approaches ranging from biochemical analyses, to cell biology, to mouse models of disease. It is hoped that the insight gained from answering these basic biological questions might lead to novel therapeutic strategies for the prevention or treatment of human disease.