13 results found
Leach DA, Mohr A, Giotis ES, et al., 2021, The antiandrogen enzalutamide downregulates TMPRSS2 and reduces cellular entry of SARS-CoV-2 in human lung cells, Nature Communications, Vol: 12, Pages: 1-12, ISSN: 2041-1723
SARS-CoV-2 attacks various organs, most destructively the lung, and cellular entry requires two host cell surface proteins: ACE2 and TMPRSS2. Downregulation of one or both of these is thus a potential therapeutic approach for COVID-19. TMPRSS2 is a known target of the androgen receptor, a ligand-activated transcription factor; androgen receptor activation increases TMPRSS2 levels in various tissues, most notably prostate. We show here that treatment with the antiandrogen enzalutamide – a well-tolerated drug widely used in advanced prostate cancer – reduces TMPRSS2 levels in human lung cells and in mouse lung. Importantly, antiandrogens significantly reduced SARS-CoV-2 entry and infection in lung cells. In support of this experimental data, analysis of existing datasets shows striking co-expression of AR and TMPRSS2, including in specific lung cell types targeted by SARS-CoV-2. Together, the data presented provides strong evidence to support clinical trials to assess the efficacy of antiandrogens as a treatment option for COVID-19.
Akram K, Yates L, Mongey R, et al., 2019, Time-lapse imaging of alveologenesis in mouse precision-cut lung slices, Bio-protocol, Vol: 9, ISSN: 2331-8325
Alveoli are the gas-exchange units of lung. The process of alveolar development,alveologenesis, is regulated by a complex network of signaling pathways that act on various cell typesincluding alveolar type I and II epithelial cells, fibroblasts and the vascular endothelium. Dysregulatedalveologenesis results in bronchopulmonary dysplasia in neonates and in adults, disrupted alveolarregeneration is associated with chronic lung diseases including COPD and pulmonary fibrosis.Therefore, visualizing alveologenesis is critical to understand lung homeostasis and for thedevelopment of effective therapies for incurable lung diseases. We have developed a technique tovisualize alveologenesis in real-time using a combination of widefield microscopy and imagedeconvolution of precision-cut lung slices. Here, we describe this live imaging technique in step-by-stepdetail. This time-lapse imaging technique can be used to capture the dynamics of individual cells withintissue slices over a long time period (up to 16 h), with minimal loss of fluorescence or cell toxicity.
Akram K, Yates L, Mongey R, et al., 2019, Live imaging of alveologenesis in precision-cut lung slices reveals dynamic epithelial cell behaviour, Nature Communications, Vol: 10, Pages: 1-16, ISSN: 2041-1723
Damage to alveoli, the gas-exchanging region of the lungs, is a component of many chronic and acute lung diseases. In addition, insufficient generation of alveoli results in bronchopulmonary dysplasia, a disease of prematurity. Therefore visualising the process of alveolar development (alveologenesis) is critical for our understanding of lung homeostasis and for the development of treatments to repair and regenerate lung tissue. Using long-term, time-lapse imaging of precision-cut lung slices, we show alveologenesis for the first time. We reveal that during this process, epithelial cells are highly mobile and we identify specific cell behaviours that contribute to alveologenesis: cell clustering, hollowing and cell extension. Using the cytoskeleton inhibitors blebbistatin and cytochalasin D, we showed that cell migration is a key driver of alveologenesis. This study reveals important novel information about lung biology and provides a new system in which to manipulate alveologenesis genetically and pharmacologically.
Zhang Y, Poobalasingam T, Yates LL, et al., 2018, Manipulation of Dipeptidylpeptidase 10 in mouse and human in vivo and in vitro models indicates a protective role in asthma, Disease Models and Mechanisms, Vol: 11, ISSN: 1754-8403
We previously identified dipeptidylpeptidase 10 (DPP10) on chromosome 2 as a human asthma susceptibility gene, through positional cloning. Initial association results were confirmed in many subsequent association studies but the functional role of DPP10 in asthma remains unclear. Using the MRC Harwell N-ethyl-N-nitrosourea (ENU) DNA archive, we identified a point mutation in Dpp10 that caused an amino acid change from valine to aspartic acid in the β-propeller region of the protein. Mice carrying this point mutation were recovered and a congenic line was established (Dpp10145D). Macroscopic examination and lung histology revealed no significant differences between wild-type and Dpp10145D/145D mice. However, after house dust mite (HDM) treatment, Dpp10 mutant mice showed significantly increased airway resistance in response to 100 mg/ml methacholine. Total serum IgE levels and bronchoalveolar lavage (BAL) eosinophil counts were significantly higher in homozygotes than in control mice after HDM treatment. DPP10 protein is present in airway epithelial cells and altered expression is observed in both tissue from asthmatic patients and in mice following HDM challenge. Moreover, knockdown of DPP10 in human airway epithelial cells results in altered cytokine responses. These results show that a Dpp10 point mutation leads to increased airway responsiveness following allergen challenge and provide biological evidence to support previous findings from human genetic studies.
Oozeer F, Yates LL, Dean C, et al., 2017, A role for core planar polarity proteins in cell contact-mediated orientation of planar cell division across the mammalian embryonic skin, SCIENTIFIC REPORTS, Vol: 7, ISSN: 2045-2322
The question of how cell division orientation is determined is fundamentally important for understanding tissue and organ shape in both healthy or disease conditions. Here we provide evidence for cell contact-dependent orientation of planar cell division in the mammalian embryonic skin. We propose a model where the core planar polarity proteins Celsr1 and Frizzled-6 (Fz6) communicate the long axis orientation of interphase basal cells to neighbouring basal mitoses so that they align their horizontal division plane along the same axis. The underlying mechanism requires a direct, cell surface, planar polarised cue, which we posit depends upon variant post-translational forms of Celsr1 protein coupled to Fz6. Our hypothesis has parallels with contact-mediated division orientation in early C. elegans embryos suggesting functional conservation between the adhesion-GPCRs Celsr1 and Latrophilin-1. We propose that linking planar cell division plane with interphase neighbour long axis geometry reinforces axial bias in skin spreading around the mouse embryo body.
Poobalasingam T, Yates LL, Walker SA, et al., 2017, Heterozygous Vangl2 looptail mice reveal novel roles for the planar cell polarity pathway in adult lung homeostasis and repair, Disease Models & Mechanisms, Vol: 10, Pages: 409-423, ISSN: 1754-8403
Lung diseases impose a huge economic and health burden worldwide. A key aspect of several adult lung diseases, such as Idiopathic pulmonary fibrosis (IPF) and Chronic Obstructive pulmonary Disease (COPD), including emphysema, is aberrant tissue repair, which leads to an accumulation of damage and impaired respiratory function. Currently, there are few effective treatments available for these diseases and their incidence is rising.The Planar Cell Polarity (PCP) pathway is critical for the embryonic development of many organs, including kidney and lung. We have previously shown that perturbation of the PCP pathway impairs tissue morphogenesis, which disrupts the number and shape of epithelial tubes formed within these organs during embryogenesis. However, very little is known about the role of the PCP pathway beyond birth, partly due to the perinatal lethality of many PCP mouse mutant lines.Here we have investigated heterozygous Looptail (Lp) mice, in which a single copy of the core PCP gene, Vangl2, is disrupted. We show that these mice are viable but display severe airspace enlargement and impaired adult lung function. Underlying these defects, we find that Vangl2Lp/+ lungs exhibit altered distribution of actin microfilaments and abnormal regulation of the actin modifying protein cofilin. In addition, we show that Vangl2Lp/+ lungs exhibit many of the hallmarks of tissue damage including an altered macrophage population, abnormal elastin deposition and elevated levels of the elastin-modifying enzyme, Mmp12, all of which are observed in the lung disease, emphysema.In vitro, VANGL2 disruption impairs directed cell migration and reduces the rate of repair following scratch wounding of human alveolar epithelial cells. Moreover, using population data from a birth cohort of young adults, all aged 31, we found evidence of an interactive effect between VANGL2 and smoking (a tissue damaging insult) on lung function. Finally, we show that that PCP genes VANGL2 and SCRIBBLE (SC
Elsum IA, Yates LL, Pearson HB, et al., 2013, Scrib heterozygosity predisposes to lung cancer and cooperates with KRas hyperactivation to accelerate lung cancer progression in vivo., Oncogene, Vol: 33, Pages: 5523-5533, ISSN: 0950-9232
Lung cancer is the leading cause of cancer deaths worldwide with non small-cell lung cancer (NSCLC) accounting for 80% of all lung cancers. Although activating mutations in genes of the RAS-MAPK pathway occur in up to 30% of all NSCLC, the cooperating genetic lesions that are required for lung cancer initiation and progression remain poorly understood. Here we identify a role for the cell polarity regulator Scribble (Scrib) in NSCLC. A survey of genomic databases reveals deregulation of SCRIB in human lung cancer and we show that Scrib+/- mutant mice develop lung cancer by 540 days with a penetrance of 43%. To model NSCLC development in vivo, we used the extensively characterized LSL-KRasG12D murine model of NSCLC. We show that loss of Scrib and activated oncogenic KRas cooperate in vivo, resulting in more aggressive lung tumors, likely due to a synergistic elevation in RAS-MAPK signaling. Finally, we provide data consistent with immune infiltration having an important role in the acceleration of tumorigenesis in KRasG12D lung tumors following Scrib loss
Yates LL, Schnatwinkel C, Hazelwood L, et al., 2013, Scribble is required for normal epithelial cell-cell contacts and lumen morphogenesis in the mammalian lung, DEVELOPMENTAL BIOLOGY, Vol: 373, Pages: 267-280, ISSN: 0012-1606
- Author Web Link
- Open Access Link
- Citations: 55
Yates LL, Dean CH, 2011, Planar polarity: A new player in both lung development and disease., Organogenesis, Vol: 7, Pages: 209-216, ISSN: 1547-6278
The clinical burden of both adult and neonatal lung disease worldwide is substantial; in the UK alone, respiratory disease kills one in four people. It is increasingly recognized that genes and pathways that regulate lung development, may be aberrantly activated in disease and/or reactivated as part of the lungs' intrinsic repair mechanisms. Investigating the genes and signaling pathways that regulate lung growth has led to significant insights into the pathogenesis of congenital and adult lung disease. Recently, the planar cell polarity (PCP) pathway has been shown to be required for normal lung development, and data suggests that this signaling pathway is also involved in the pathogenesis of some lung diseases. In this review, we summarize current evidence indicating that the PCP pathway is required for both lung development and disease.
Yates LL, Papakrivopoulou J, Long DA, et al., 2010, The planar cell polarity gene Vangl2 is required for mammalian kidney-branching morphogenesis and glomerular maturation, HUMAN MOLECULAR GENETICS, Vol: 19, Pages: 4663-4676, ISSN: 0964-6906
- Author Web Link
- Open Access Link
- Citations: 84
Yates LL, Schnatwinkel C, Murdoch JN, et al., 2010, The PCP genes Celsr1 and Vangl2 are required for normal lung branching morphogenesis, HUMAN MOLECULAR GENETICS, Vol: 19, Pages: 2251-2267, ISSN: 0964-6906
- Author Web Link
- Open Access Link
- Citations: 114
Yates L, McMurray F, Zhang Y, et al., 2009, ENU mutagenesis as a tool for understanding lung development and disease Biochemical Society Transactions 37: 838–842.
Warr N, Siggers P, Bogani D, et al., 2009, Sfrp1 and Sfrp2 are required for normal male sexual development in mice, DEVELOPMENTAL BIOLOGY, Vol: 326, Pages: 273-284, ISSN: 0012-1606
- Author Web Link
- Citations: 72
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