Cellular & Molecular Structure & Function
The cell is the basic unit of all life forms. To understand the cell, we must know all its components & have a detailed mechanistic understanding of how these function.
Our cellular and molecular structure and function research interests range from computational protein folding to stem cell biology. Despite the breadth, we can identify many themes, all of which centre on understanding fundamental mechanisms. Several labs focus on neuronal development and neuronal tissue function, such as the study of neuronal stem cell generation, axon guidance mechanisms, and the molecular basis for neural network formation. Central to these efforts is the study of stem cells and the use of several different animal models. We leverage cutting-edge techniques involving laser optics and optogenetics to study higher-order functions such as learning, memory and locomotion. We also use stem cells and animal models, including the zebrafish, to study development and disease in other systems and tissues, including the heart and kidney. Collectively, we expect the advances emerging from these efforts to contribute to novel approaches to treating neural and heart tissue damage, brain cancers in children and Alzheimer's disease in the elderly, to name just a few.
Genome stability through successive cell divisions is central to maintaining normal cellular function. Not surprisingly, DNA damage and the gain or loss of chromosomes or portions of them are hallmarks of cancer. Several MoGen labs are working to understand DNA repair mechanisms and the processes that ensure proper chromosome replication and segregation. In one collaborative effort, we used functional genomics, microscopy and mass-spectrometry to study centrosome biogenesis, an essential component in regulating cell division. In another collaboration, we utilized cell-based approaches and x-ray crystallography to determine how DNA repair enzymes are recruited to double-strand breaks.
Regulation of gene expression is critical at all stages in the life-cycle of a living organism, and control at both transcriptional and translational levels is the focus of many members of our Department. The core of the effort is identifying and characterizing the DNA- and RNA-binding proteins involved in controlling these processes. Over the past few decades, we have begun to appreciate the critical roles of small RNAs in gene regulation. A new paradigm for small RNA-mediated gene regulation is starting to emerge from recent work by MoGen labs. Splicing of pre-mRNA enables both gene regulation and the generation of various protein isoforms, with exciting new research in this area from MoGen members shedding light on how microexon splicing is controlled in neural development and how the process is misregulated in autism.
The study of protein structure and protein interactions represents another theme among group members. Collectively, a wide range of biophysical techniques, including NMR and x-ray crystallography, and computational approaches, are being used in this research. We study protein folding and quality control, protein-protein interactions, macromolecular assemblies, G protein-coupled receptors, ion transporters, virus-receptor interactions and protein kinases, and more. Intrinsically disordered proteins are now known to mediate cross-talk between signalling pathways. Structural insights into how they perform this role represent one example of cutting-edge research that has recently emerged from our group. MoGen labs also focus on developing novel protein and small-molecule human therapeutics. These efforts are using protein engineering to develop novel antibody therapeutics, using bacteriophage as antibiotics, and identifying new drug targets using the membrane yeast two-hybrid assay. Novel functional proteomic approaches also help discover and characterize protein-drug and protein-ligand interactions, which promises to uncover new uses for already approved small-molecule therapeutics.