Ubiquitin-proteasome system

The first area of focus is understanding the role of protein processing and degradation with in the endosomal/lysosomal pathway and in the cytoplasm. The lysosomal pathway is responsible for degradation of extracellular proteins within the cytoplasm and the major (and best understood) proteolytic system is the ubiquitin-proteasome system. This pathway involves dozens of distinct components and is involved in the degradation of short lived and abnormal proteins. Using eukaryotic mutants of the pathway and specific antibodies to components of the pathway, the Schwartz laboratory identified a linkage between these two systems. Furthermore, using in vitro reconstituted systems they have begun to dissect the structural elements of substrates (including oncoproteins) that signal their processing and degradation. Our recent focus is on the role of the ubiquitin-proteasome in transcription-factor (e.g., myoD, E2A) degradation in the cytoplasm and nucleus and the molecular mechanisms involved.

Cell biology of preterm birth: trophoblast and uterine biology

We also use cell and molecular biology coupled with biomedical engineering to study etiologies of preterm birth. The placenta is a specialized organ that serves essential roles during fetal development and birth. During placental development cytotrophoblast cells proliferate and fuse to for a multi-nucleated syncytiotrophoblast. We showed that cyclic AMP-signaling enhances syncytia formation in BeWo cytotrophoblasts and are elucidating the mechanisms of syncytia formation. In addition, the uterus, an electrical organ, matures and triggers electrical-mechanical coupling essential to the birth process. We have developed a non-invasive technology to map the electrical activity of the gravid uterus in real time (EMMI, electromyometrial imaging) and are elucidating its abnormalities in preterm labor.

Receptor-mediated endocytosis

The second area is the cell and molecular biology of receptor-mediated endocytosis and its regulation. The Schwartz research group has identified a huge, multifunctional cell surface endocytosis receptor (LRP) which governs the plasma clearance of several physiologically important ligands including the plasminogen activators t-PA and u-PA, as well as apolipoprotein E, lipoprotein lipase and, most recently, TFPI (tissue factor pathway inhibitor), a regulator of blood coagulation. Our approaches include immuno-electron microscopy, as well as in vivo gene targeting. Recent focus is directed to regulation of LRP and ligand trafficking and turnover.