Biology subjects

Howell, R.

Publications and source records attributed to Howell, R..

3 recordsLinked to original sources

bioRxiv2022

A dual role for CRTH2 in acute lung injury

Acute respiratory distress syndrome (ARDS) is a life-threatening clinical condition defined by rapid-onset respiratory failure following acute lung injury (ALI). The high mortality rate and rising incidence of ARDS due to COVID-19 make it an important research priority. Here we sought to investigate the role of chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) in ARDS. CRTH2 is a G protein-coupled receptor best studied in the context of type 2 immunity, but it also exerts effects on neutrophilic inflammation. To evaluate its role in mouse models of ARDS, we first examined its expression pattern on murine neutrophils. We found it is expressed on neutrophils, but only after extravasation into the lung. Next, we showed that CRTH2 expression on extravasated lung neutrophils promotes cell survival, as genetic deletion of CRTH2 and pharmacologic inhibition of CRTH2 using fevipiprant both led to increased apoptosis in vitro. We then evaluated the role of CRTH2 in vivo using a murine model of LPS-induced ALI. In line with the pro-inflammatory effects of CRTH2 in vitro, we observed improvement of lung injury in CRTH2-deficient mice in terms of vascular leak, weight loss and survival after LPS administration. However, neutrophilic inflammation was elevated, not suppressed in the CRTH2 KO. This finding indicated a second mechanism offsetting the pro-survival effect of CRTH2 on neutrophils. Bulk RNAseq of lung tissue indicated impairments in type 2 immune signaling in the CRTH2 KO, and qPCR and ELISA confirmed downregulation of IL-4, which is known to suppress neutrophilic inflammation. Thus, CRTH2 may play a dual role in ALI, directly promoting neutrophil cell survival, but indirectly suppressing neutrophil effector function via IL-4.

immunology↗

bioRxiv2021

Executable Network of SARS-CoV-2-Host Interaction Predicts Drug Combination Treatments

The COVID-19 pandemic has pushed healthcare systems globally to a breaking point. The urgent need for effective and affordable COVID-19 treatments calls for repurposing combinations of approved drugs. The challenge is to identify which combinations are likely to be most effective and at what stages of the disease. Here, we present the first disease-stage executable signalling network model of SARS-CoV-2-host interactions used to predict effective repurposed drug combinations for treating early- and late-stage severe disease. Using our executable model, we performed in silico screening of 9870 pairs of 140 potential targets and have identified 12 new drug combinations. Camostat and Apilimod were predicted to be the most promising combination in effectively supressing viral replication in the early stages of severe disease and were validated experimentally in human Caco-2 cells. Our study further demonstrates the power of executable mechanistic modelling to enable rapid pre-clinical evaluation of combination therapies tailored to disease progression. It also presents a novel resource and expandable model system that can respond to further needs in the pandemic.

systems biology↗

bioRxiv2019

Female mice are resilient to age-related decline of substantia nigra dopamine neuron firing parameters

The degeneration of substantia nigra (SN) dopamine neurons is a central feature in the pathology associated with Parkinsons disease, which is characterized by progressive loss of motor and cognitive functions. The largest risk factors for Parkinsons disease are age and sex; most cases occur after age 60 and males have nearly twice the incidence as females. While much research in Parkinsons has focused on the mechanisms underlying dopamine neuron degeneration, very little work has considered the influence of these two risk factors to disease risk and presentation. In this work, we performed whole cell patch clamp recordings in brain slices to study the alterations in intrinsic firing properties of single dopamine neurons in C57BL/6 mice across ages and between sexes. We observed a progressive decline in dopamine neuron firing activity in males by 18 months of age, while dopamine neurons from females remained largely unaffected. A semiquantitative analysis of midbrain dopamine neuron populations revealed a slight decrease only in substantia nigra dopamine neurons in males, while females did not change. This was also accompanied by increases in the expression of genes that have been linked to Parkinsons including PTEN-induced kinase 1 (PINK1) in both males and females, and the ubiquitin ligase parkin, primarily in the substantia nigra of males. These impairments in dopamine neuron function in males may represent a vulnerability to further insults that could predispose these cells to neurodegenerative diseases such as in Parkinsons.

neuroscience↗