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Mechanisms of cilia biogenesis and signalling

Cilia are sensory organelles that detect mechanical and chemical stimuli from the environment. They arise from centrioles and function as “antennae” that receive and integrate extracellular signals. The Hedgehog pathway, a developmental pathway implicated in cancer, is one important example of a signalling pathway whose function depends on the presence of primary cilia. Primary cilia are present in almost every cell, and their disruption results in a number of illnesses called ciliopathies which include retinal degeneration, obesity, diabetes and polycystic kidney disease. Previously, we identified a novel group of centriolar distal appendage proteins (DAPs) and defined their role in ciliogenesis (Tanos et al, 2013, Yang et al, 2018). These proteins now have been shown to be mutated in diverse ciliopathies including infantile nephronophthisis, intellectual disability (Failler et al), and oro-facio-digital syndrome type IX featuring midline cleft, microcephaly, and colobomatous microphathalmia/anophthalmia (Adly et al 2014). Thus, to better understand the molecular basis of these diseases, it is critical to understand how centrioles promote ciliogenesis and how they regulate ciliary signalling. Recently, we have shown that a centriolar kinase, TTBK2, supports ciliary vesicle formation and ciliary assembly (Lo et al, 2019) and have also demonstrated a role for primary cilia in drug resistance in cancer (Jenks et al, 2018).

The objectives of this project are to understand the molecular complexes that regulate cilia biogenesis and signalling and to understand how their misregulation can lead to disease. We will focus on the regulation of centriole distal appendage proteins (DAPs).

We will use CRISPR/Cas9-engineered isogenic cell lines deficient in specific centriolar proteins, including DAPs, to understand how they are recruited to centrioles and how they regulate ciliogenesis. To this end, we will use various biochemical, cell biology and microscopy techniques. We will have access to animal models in collaboration with a number of labs at Brunel. At the end of the project the student will have developed tools to carry out research independently, and have substantial practical and conceptual knowledge of the cilia field.

References:

Barbara E. Tanos, Hui-Ju Yang, Rajesh Soni, Won-Jing Wang, Frank P. Macaluso, John M. Asara and Meng-Fu Bryan Tsou.Centriole distal appendages promote membrane docking, leading to cilia initiation. 2013. Genes Dev 27: 163-168.

T. Tony Yang, Weng Man Chong, Won-Jing Wang, Gregory Mazo, Barbara Tanos, Zhengmin Chen, Thi Minh Nguyet Tran, Yi-De Chen, Rueyhung Roc Weng, Chia-En Huang, Wann-Neng Jane, Meng-Fu Bryan Tsou, Jung-Chi Liao. Architecture of mammalian centriole distal appendages supports a matrix that gates the primary cilium. 2018. Nature Communications. 2018 May 22;9(1):2023. doi: 10.1038/s41467-018-04469-1. doi: https://doi.org/10.1101/193474

Failler M, Gee HY, Krug P, Joo K, Halbritter J, Belkacem L, Filhol E, Porath JD, Braun DA, Schueler M, Frigo A, Alibeu O, Masson C, Brochard K, Hurault de Ligny B, Novo R, Pietrement C, Kayserili H, Salomon R, Gubler MC, Otto EA, Antignac C, Kim J, Benmerah A, Hildebrandt F, Saunier S. Mutations of CEP83 cause infantile nephronophthisis and intellectual disability. Am J Hum Genet. 2014 Jun 5;94(6):905-14. doi: 10.1016/j.ajhg.2014.05.002. Epub 2014 May 29. PMID: 24882706.

Adly N, Alhashem A, Ammari A, Alkuraya FS. Ciliary genes TBC1D32/C6orf170 and SCLT1 are mutated in patients with OFD type IX. Hum Mutat. 2014 Jan;35(1):36-40. doi: 10.1002/humu.22477.

Chien-Hui Lo, I-Hsuan Lin, T. Tony Yang, Yen-Chun Huang, Barbara E. Tanos, Yeou-Guang Tsay, Jung-Chi Liao and Won-Jing Wang. TTBK2 phosphorylates CEP83 in promoting cilia initiation. 2019. Journal of Cell Biology. 2019 Aug 27. PMID:31455668

Andrew D. Jenks, Simon Vyse, Jocelyn P. Wong, Deborah Keller, Tom Burgoyne, Amelia Shoemark, Maike de la Roche, Martin Michaelis, Jindrich Cinatl, Paul H. Huang and Barbara E. Tanos. Primary cilia mediate diverse kinase inhibitor resistance mechanisms in cancer. 2018. 2018. Cell Reports. 2018 Jun 5;23(10):3042-3055. doi: 10.1016/j.celrep.2018.05.016.

How to apply

If you are interested in applying for the above PhD topic please follow the steps below:

  1. Contact the supervisor by email or phone to discuss your interest and find out if you woold be suitable. Supervisor details can be found on this topic page. The supervisor will guide you in developing the topic-specific research proposal, which will form part of your application.
  2. Click on the 'Apply here' button on this page and you will be taken to the relevant PhD course page, where you can apply using an online application.
  3. Complete the online application indicating your selected supervisor and include the research proposal for the topic you have selected.

Good luck!

This is a self funded topic

Brunel offers a number of funding options to research students that help cover the cost of their tuition fees, contribute to living expenses or both. See more information here: https://www.brunel.ac.uk/research/Research-degrees/Research-degree-funding. The UK Government is also offering Doctoral Student Loans for eligible students, and there is some funding available through the Research Councils. Many of our international students benefit from funding provided by their governments or employers. Brunel alumni enjoy tuition fee discounts of 15%.


Dr Barbara Tanos - A global nomad, Dr Barbara Tanos received her undergraduate degree from the University Buenos Aires, Argentina, and her PhD in Molecular Cancer Biology from Duke University in North Carolina (USA). As a graduate student in the laboratory of Dr Ann Marie Pendergast, Dr Tanos became interested in how signal transduction pathways regulate basic biological processes such as the trafficking of growth factor receptors throughout the cell. During her graduate studies, Dr Tanos uncovered a novel role of Abl tyrosine kinases in the regulation of the epidermal growth factor receptor (EGFR) internalization through specific phosphorylation of a tyrosine residue and through the disruption of the EGFR/Cbl interaction.  During her postdoc, Dr. Tanos began conceptualizing the idea that specific signals that drive epithelial polarity can be co- opted by cancer cells to optimize the remodeling of tumor tissue architecture, she trained with world-renowned cell biologist Dr. Enrique Rodriguez-Boulan at WCMC-NY, and wrote a review entitled “The epithelial polarity program: machineries involved and their hijacking by cancer,” and also uncovered a novel role for the scaffold protein IQGAP1 in barrier function during the establishment of epithelial polarity. After this, she began to appreciate the importance of understanding signaling from centrioles and cilia, which she hypothesized, could function as signaling hubs. Since little was known about these organelles, Barbara went to the laboratory of Dr. Bryan Tsou, an expert in the field, to learn key aspects of centrosome and cilia biology. There, Barbara identified a novel group of centriolar distal appendage proteins required for cilia formation, and uncovered the mechanism and cell cycle regulation of centriole docking to the plasma membrane. This work was published in Genes and Development, has been highly cited and it is considered to be a hallmark paper in the field. The proteins she described have now been causally linked to hereditary syndromes involving cilia defects (ciliopathies). At Brunel University, Dr Tanos’s lab focuses on understanding the mechanisms of regulation of centrioles and cilia, how they function as signalling platforms, and what the consequences of their misregulation are in disease. Using a unique mix of expertise in signal transduction, biochemistry, cancer biology and cell biology she uses this information to find and exploit therapeutic opportunities both for cancer and ciliopathies. Work from the Tanos Lab,  has been recently published in Cell Reports, describing a truly novel and fascinating story on the role of primary cilia in promoting resistance to a variety of cancer drugs: https://www.cell.com/cell-reports/fulltext/S2211-1247(18)30749-6, and was featured in the MRC and other news websites: http://bpod.mrc.ac.uk/archive/2018/6/28, https://www.icr.ac.uk/news-archive/stunting-cell-antennae-could-make-cancer-drugs-work-again. and Dr. Tanos was interviewed on the radio, http://news.radiojackie.com/2018/06/the-institute-of-cancer-research-in.html External website: tanoslab.org