Research Topics
Department of Cell & Structural Biology
Ph.D. (1993) Rice University
Research Topics
Research Interests
Our laboratory is primarily
interested in signaling mechanisms that regulate fundamental cellular processes
in mammals such as growth, proliferation and differentiation. Specifically, our
current efforts are focused on the rapamycin-sensitive signaling network that
governs a wide range of cellular functions from translation, transcription to
anti-apoptosis. Aided by a wide range of experimental approaches from molecular
biology, biochemistry, cell biology, to genetics/transgenics and genomics, two
major areas of research ongoing in the lab concern the mechanisms of rapamycin-sensitive
signaling in cell proliferation and skeletal muscle development.
The bacterial macrolide rapamycin, initially isolated as an anti-fungal agent, has elicited tremendous medical interests due to its multitude of activities. As an immunosuppressant, rapamycin is used to prevent graft rejection after transplantation. A recent clinical trial has demonstrated great efficacy of rapamycin-eluting stents in preventing restenosis (re-blockage of arteries after angioplasty procedures). Furthermore, rapamycin and its analogue CCI-779 are promising anti-cancer drugs, potently inhibiting a wide range of human tumor cell lines and xenografts. All these clinically relevant activities derive from rapamycin's inhibitory action on cell growth and proliferation. A clear picture of the molecular circuitry of the rapamycin-sensitive signaling network will not only advance our understanding of various cellular regulations, but also facilitate the future design and refinement of therapeutic strategies.
A key player in the rapamycin-sensitive signal transduction is the mammalian target of rapamycin (mTOR; also named FRAP). mTOR belongs to a novel family of protein kinases that have sequence homology to lipid kinases. (Other mammalian members of this family include ATM, ATR, DNA-PK, etc.) Based on accumulating biochemical and cellular evidence, an emerging hypothesis is that mTOR, as a large protein of 290 kDa, is a multi-functional protein that serves a scaffolding function to components of intersecting signaling pathways. Recent findings from our laboratory have shed new light on the complexity of this network. The lipid second messenger, phosphatidic acid (PA), has been found to mediate mitogenic activation of mTOR signaling by directly interacting with the rapamycin-binding domain in mTOR, thus bringing several potential upstream regulators into the mTOR circuitry. Furthermore, mTOR undergoes constant cytoplasmic-nuclear shuttling, which may imply a coordination of multiple functions that mTOR supports in various cellular compartments. mTOR and the rapamycin-sensitive pathway(s) also play essential roles in the initiation of skeletal muscle differentiation and hypertrophy, possibly through mechanisms distinct from those governing proliferation. Dissection of the mTOR regulatory circuitry in myogenesis promises to unravel the intricate relationship between myoblast proliferation, initiation of the differentiation program, and further enhancement of myofiber formation, which is directly relevant to health-related issues such as exercise-induced muscle hypertrophy and aging-related muscle atrophy.
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