G-310 Health Sciences Building
Research in my lab is focused on defining novel signaling and transcriptional regulatory mechanisms that underlie cardiac hypertrophy and heart failure. We take multi-disciplinary approaches including biochemistry, molecular and cell biology, molecular genetics, and system physiology to understand the molecular basis of heart disease using model systems ranging from yeast cell system to genetic mouse models.
We are particularly interested in elucidating novel cell signaling mechanisms in the heart involving protein kinases (e.g, PKC, ASK1, and TAK1) and phosphatases (e.g, PP1, PP2A, and calcineurin). Our ongoing studies investigate the novel TAK1 (TGFbeta activated Kinase 1, as known as Map3k7) signaling network as a central regulator of the cardiac myocyte growth and death using our newly generated cardiac-specific transgenic and gene targeted mouse models. My laboratory also seeks to understand transcriptional regulatory mechanisms of heart disease, with a focus on transcription factors NFAT and NFkB. Other ongoing studies investigate programmed necrosis signaling in the pathogenesis of pathological cardiac remodeling and heart failure.
There are 3 major research areas involving multiple projects:
A. Molecular mechanisms of cardiac hypertrophy: Our current project tests the hypothesis that TAK1 controls an intracellular signaling network that is required for hypertrophic growth of the heart in vivo, using our newly developed inducible cardiac-specific TAK1 transgenic mice. We will also define potential crosstalk mechanisms between TAK1 and other hypertrophic signaling pathways including calcineurin/ NFAT and NFkB in the heart by using genetic and molecular approaches.
B. Molecular regulation of cardiac cell survival and death: Our very recent studies identified TAK1 as a critical “molecular switch” in regulating programmed necrosis (necroptosis) in cardiac myocytes as well as other cell systems. This project investigates molecular mechanisms by which TAK1 regulates RIP1/RIP3-mediated necroptosis signaling. Another project investigates if and how TAK1 regulates mitochondria necrotic pathway. Key signaling molecules such as cyclophilin D and Bax/Bak as well as ROS production as potential signaling effectors will be examined.
C. Programmed necrosis (necroptosis) and heart disease: We propose to test the hypothesis that RIP3-mediated programmed necrosis prominently contributes to the pathogenesis of heart failure, using RIP3 knockout and transgenic mice (both are available in the lab). Another research focus is to determine key components of the programmed necrosis signaling network. We also investigate the interconnection and crosstalk between apoptotic and necrotic cell death pathways.
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Fred Hutchison Cancer Research Center | University of Washington
Institute for Systems Biology | Seattle Biomed