|Professor, Microbiology, Immunology & Molecular Genetics|
|Member, Biochemistry, Biophysics & Structural Biology GPB Home Area, California NanoSystems Institute, Cell & Developmental Biology GPB Home Area, Immunity, Microbes & Molecular Pathogenesis GPB Home Area, Microbiology, Immunology & Molecular Genetics|
The eukaryotic flagellum (synonymous with cilium) is a biological nanomachine, composed of thousands of interconnected parts. Flagella and cilia perform essential motility and signaling functions, are conserved in all eukaryotic lineages, and are considered to have been present on the last eukaryotic common ancestor.
Proteomics and genomics have provided an inventory of flagellar proteins, but we lack knowledge of how these are assembled into supramolecular structures that operate individually and collectively to drive motility and signaling by the flagellum. This presents a critical gap in our understanding of one of the most iconic features of eukaryote biology. To fill this gap, we use cryoelectron microscopy (cryoEM) and tomography (cryoET) to determine the 3D architecture of the flagellum. We also employ proteomics, super-resolution microscopy, high-speed video microscopy and animal imaging to define the spatial distribution of proteins within flagellum micro-domains, investigate mechanisms of microbial cell and signaling, and determine how the flagellum controls virulence of microbial pathogens. Our goal is to provide a structural foundation for defining flagellum motility and signaling mechanisms at the molecular level, with models being formally tested through genetic manipulation of component parts.
As an experimental system, my group employs African trypanosomes, parasites that present a global public health burden and limit economic development in some of the most impoverished regions on the planet. The flagellum directs parasite motility and extracellular sensing and is thus essential for transmission and pathogenic capacity of these deadly organisms.
The trypanosome flagellum is also conserved with the human cilium (aka flagellum), which is essential for normal development and physiology. Indeed, cilium defects underlie a broad spectrum of inherited diseases, including retinopathy, renal failure, skeletal abnormalities and obesity. Therefore, beyond their medical and economic importance, trypanosomes are an important model system for studying flagellum/cilium biology. They are easily cultured for biochemical studies and possess a potent array of molecular genetic tools for targeted gene knockout and inducible RNAi. The genome is fully sequenced and annotated and systems biology approaches, e.g. transcriptomics, quantitative proteomics and high-throughput RNAi screens, are well established. Therefore, in addition to host-pathogen interaction, we use our studies to advance understanding of inherited diseases in humans, and provide insights into fundamental features of eukaryotic cell biology.