Importance of Transition Metals in Mammalian Development
My lab is investigating the biological roles of transition metals, such as Cu, Zn, Co, and Mn, in the development of mammalian cells. Metals play many critical roles in biology as cofactors for a variety of enzymes that are necessary for energy production, tissue maturation, signal transduction and oxidative stress resistance. Metal homeostasis requires chelation by high-affinity binding molecules, transport and sensing by transcriptional regulators to maintain low levels of free metals, as free metals participate in different toxic reactions. How organisms acquire these micronutrients and distribute them to specific cellular compartments or target proteins are subjects of intense scientific interest. Moreover, little is known about how metals and the proteins that handle and distribute them participate in processes that regulate normal growth and development. Eukaryotic genomes encode a wide variety of metal transporters and metalloproteins. Although their biochemical and metal binding properties are relatively well understood, little is known about the fine-tuned regulation of their expression, specificity for metal transport, and the redundancy of functions in the context of cell differentiation and development.
My lab conducts systematic studies that combine a variety of molecular and cell biology techniques into biological models, including established cell lines and primary cultures. We incorporate diverse biochemistry techniques and combine with high resolution cutting edge synchrotron-based X-ray fluorescence spectroscopy. In particular, we study skeletal muscle differentiation as muscle present an elevated intrinsic need for transition metals like Cu for proper function. This ion is required for mitochondrial energy production as a fundamental component of cytochrome c oxidase which is elevated during the course of differentiation. We hypothesize that the proper cellular distribution of Cu+ has a leading role in the differentiation of the muscle lineage. We have evidence that support different cellular roles for Cu in addition to energy production. Moreover, we hypothesize that diverse devastating myopathies are associated with Cu deficiencies at different levels, from mitochondrial Cu-transport and function to general cellular failure in Cu homeostasis and gene regulation. We hope to provide novel molecular mechanisms that help to understand the basis of muscular phenotypes observed in mitochondrial myopathies and also in Menkes’ and Wilson’s disease patients.
Identification of a Chemical Probe for Family VIII Bromodomains through Optimization of a Fragment Hit.