Centrioles are cellular nanomachines that nucleate and organize centrosomes and cilia. Defects in centrioles contribute to both cancer and ciliopathies. Ciliopathies are a general class of human maladies that include child birth defects, mental retardation, polydactyl, blindness, obesity, and polycystic kidneys. However, the mechanics of centriole formation that, when defective, contribute to the above pathologies are not well understood. Our long term goals are to understand the etiology of such defects. Toward this goal, we will study two important events in centriole formation and function;assembly and stabilization. Both of these events are vital for centrosomes and cilia. An essential centriole structure that is required for both of these events is the cartwheel. To elucidate the molecular assembly of a cartwheel, biochemical, molecular-genetic, and quantitative imaging tactics will be employed. First, we will determine how a novel complex of cartwheel components stabilizes centrioles. Second, we will define how and when protein components interact to build the cartwheel and centriole architecture. Third, one member of the stability complex is Bld10/Cep135 that, in addition to its stability role, is essential for centriole assembly. Bld10's roles in centriole function will be determined by separating its functions in centriole assembly and maintenance and identifying the proteins it interacts with to perform these functions. We will establish the key proteins and the mechanisms for cartwheel and centriole assembly into a stable structure. Building on this stable structure, we can then define how this platform nucleates cilia and centrosomes. This proposal will develop our long term goals to reconstitute cartwheel and centriole assembly and to understand how defects in these processes cause human disease. Our studies will be carried out by a collaborative group of researchers. These studies will provide excellent training experiences for undergraduate and graduate students and postdoctoral researchers and professional research assistants. Collaborations with other labs that include computational modeling, quantitative image analysis, and proteomics will expand the impact of our studies.
Centrioles are required to build centrosomes and cilia that are important for chromosome segregation, cell signaling, and extracellular fluid movement. Defects in centrosomes and cilia cause devastating human diseases, including cancer, obesity, polycystic kidneys, respiratory illness, blindness, and mental retardation.
Our research aims to discover the etiology of such maladies.
| Louka, Panagiota; Vasudevan, Krishna Kumar; Guha, Mayukh et al. (2018) Proteins that control the geometry of microtubules at the ends of cilia. J Cell Biol 217:4298-4313 |
| Galati, Domenico F; Sullivan, Kelly D; Pham, Andrew T et al. (2018) Trisomy 21 Represses Cilia Formation and Function. Dev Cell 46:641-650.e6 |
| Baschal, Erin E; Terhune, Elizabeth A; Wethey, Cambria I et al. (2018) Idiopathic Scoliosis Families Highlight Actin-Based and Microtubule-Based Cellular Projections and Extracellular Matrix in Disease Etiology. G3 (Bethesda) 8:2663-2672 |
| Kendrick, Agnieszka A; Schafer, Johnathon; Dzieciatkowska, Monika et al. (2017) CD147: a small molecule transporter ancillary protein at the crossroad of multiple hallmarks of cancer and metabolic reprogramming. Oncotarget 8:6742-6762 |
| Garcia 3rd, Galo; Finnigan, Gregory C; Heasley, Lydia R et al. (2016) Assembly, molecular organization, and membrane-binding properties of development-specific septins. J Cell Biol 212:515-29 |
| Hudish, Laura I; Galati, Domenico F; Ravanelli, Andrew M et al. (2016) miR-219 regulates neural progenitors by dampening apical Par protein-dependent Hedgehog signaling. Development 143:2292-304 |
| Wall, Kathryn P; Pagratis, Maria; Armstrong, Geoffrey et al. (2016) Molecular Determinants of Tubulin's C-Terminal Tail Conformational Ensemble. ACS Chem Biol 11:2981-2990 |
| Ruehle, Marisa D; Orias, Eduardo; Pearson, Chad G (2016) Tetrahymena as a Unicellular Model Eukaryote: Genetic and Genomic Tools. Genetics 203:649-65 |
| Galati, Domenico F; Mitchell, Brian J; Pearson, Chad G (2016) Subdistal Appendages Stabilize the Ups and Downs of Ciliary Life. Dev Cell 39:387-389 |
| Bayless, Brian A; Galati, Domenico F; Junker, Anthony D et al. (2016) Asymmetrically localized proteins stabilize basal bodies against ciliary beating forces. J Cell Biol 215:457-466 |
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