Publications by authors named "Ruby E Dawson"

2 Publications

  • Page 1 of 1

IL-6 family cytokines in respiratory health and disease.

Cytokine 2021 Apr 16:155520. Epub 2021 Apr 16.

Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia; Department of Molecular and Translational Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia. Electronic address:

Chronic lung diseases including asthma, chronic obstructive pulmonary disease (COPD) and lung fibrosis represent a major burden on healthcare systems with limited effective therapeutic options. Developing effective treatments for these debilitating diseases requires an understanding of how alterations at the molecular level affect lung macroscopic architecture. A common theme among these lung disorders is the presence of an underlying dysregulated immune system which can lead to sustained chronic inflammation. In this respect, several inflammatory cytokines have been implicated in the pathogenesis of lung diseases, thus leading to the notion that cytokines are attractive therapeutic targets for these disorders. In this review, we discuss and highlight the recent breakthroughs that have enhanced our understanding of the role of the interleukin (IL)-6 family of cytokines in lung homeostasis and chronic diseases including asthma, COPD, lung fibrosis and lung cancer.
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http://dx.doi.org/10.1016/j.cyto.2021.155520DOI Listing
April 2021

Functional screening of GATOR1 complex variants reveals a role for mTORC1 deregulation in FCD and focal epilepsy.

Neurobiol Dis 2020 02 19;134:104640. Epub 2019 Oct 19.

School of Medicine, University of Adelaide, Adelaide, SA 5005, Australia; Robinson Research Institute, University of Adelaide, Adelaide, SA 5005, Australia; Precision Medicine Theme, South Australia Health and Medical Research Institute, Adelaide, SA 5000, Australia. Electronic address:

Mutations in the GAP activity toward RAGs 1 (GATOR1) complex genes (DEPDC5, NPRL2 and NPRL3) have been associated with focal epilepsy and focal cortical dysplasia (FCD). GATOR1 functions as an inhibitor of the mTORC1 signalling pathway, indicating that the downstream effects of mTORC1 deregulation underpin the disease. However, the vast majority of putative disease-causing variants have not been functionally assessed for mTORC1 repression activity. Here, we develop a novel in vitro functional assay that enables rapid assessment of GATOR1-gene variants. Surprisingly, of the 17 variants tested, we show that only six showed significantly impaired mTORC1 inhibition. To further investigate variant function in vivo, we generated a conditional Depdc5 mouse which modelled a 'second-hit' mechanism of disease. Generation of Depdc5 null 'clones' in the embryonic brain resulted in mTORC1 hyperactivity and modelled epilepsy and FCD symptoms including large dysmorphic neurons, defective migration and lower seizure thresholds. Using this model, we validated DEPDC5 variant F164del to be loss-of-function. We also show that Q542P is not functionally compromised in vivo, consistent with our in vitro findings. Overall, our data show that mTORC1 deregulation is the central pathological mechanism for GATOR1 variants and also indicates that a significant proportion of putative disease variants are pathologically inert, highlighting the importance of GATOR1 variant functional assessment.
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http://dx.doi.org/10.1016/j.nbd.2019.104640DOI Listing
February 2020