My laboratory is interested in the regulatory interfaces between novel lipid-mediated signal transduction pathways and important cellular functions. The focus of our work is the phosphatidylinositol/ phosphatidylcholine transfer proteins (PITPs), a ubiquitous but enigmatic class of proteins. Ongoing projects in the laboratory derive from a multidisciplinary approach that encompasses biochemical characterization of novel members of the metazoan PITP family, and the application of genetic, molecular and biophysical approaches to detailed structural and functional analyses of PITPs.
The laboratory breaks down into two groups:
a) The Yeastly Group: This group studies the mechanism of function of fungal and plant PITPs, and:
b) The Mammalian Group: This group is involved in the mammalian projects in lab that include generation of knockout mice and analysis of functions of specific PITP isoforms in the mammal as well as apicomplexan organisms like Toxoplasma gondii.
Our collective evidence indicates that PITPs coordinate key interfaces of lipid-driven metabolic reactions and intracellular signaling pathways in both yeast and mammals. Inappropriate regulation of these interfaces compromises membrane trafficking events, growth factor receptor function, cell growth control, and regulation of key developmental pathways. Because defects in any one of these pathways define recognized mechanisms cancer-potentiating mechanisms, PITPs represent essentially unstudied regulators whose dysfunction is likely to influence the activities of cellular processes required for cellular homeostasis.
Of additional interest is our recent finding that one of our PITP-deficient mouse lines potentially provides a unique model for chylomicron retention disease, hypoglycemia and brain inflammatory disease. Relevant approaches that the laboratory employs include: molecular biology, protein and lipid biochemistry, confocal and electron microscopy, mouse gene knockout technology, and classical and molecular genetics. The lab is also developing new approaches for rapidly and confidently identifying the first small molecule inhibitors directed against target PITPs of interest and other key enzymes of lipid metabolism.
We are also collaborating with Dr. Zhigang Xie on projects concerning the role of lipid signaling and metabolism in neural stem cells during mammalian brain development. Maintaining the balance between neural stem cell self-renewal and differentiation is important for the production of correct type and number of neurons and, therefore, the function of the brain. Lipid signaling and metabolism have been implicated in developmental brain disorders, and are known to play a critical role in cellular functions, such as membrane trafficking, that are key to neural stem cell homeostasis. However, the role of lipid signaling and metabolism in neural stem cells remains largely unclear. Working together with the Xie lab, we use knockout mice and an in utero electroporation technique to investigate how lipid signaling and metabolism regulate neural stem cells and brain development in vivo.