Prof Rosemary Dorrington
This research program aims to develop a fundamental understanding of the molecular biology of tetraviruses as a model system for studying the biology of (+ve) ssRNA viruses that infect insects. Tetraviruses infect the larvae of lepidopteron insects (butterflies and moths) and many of their hosts are important agricultural pets. Research in the group focuses in particular on the molecular mechanisms employed by these viruses to redirect the metabolism of their host cells to support the viral lifecycle. The increasing prevalence of insect--borne RNA viruses (arboviruses) e.g. Rift Valley Fever Virus, West Nile Fever Virus and Dengue Virus, together with the lack of effective vaccines and antiviral therapies highlight the importance of understanding the interactions between RNA viruses and their hosts particularly in the insect vectors. Research projects in the group include: (1) fundamental studies on the subcellular localization of tetravirus replication and the interactions between viral and host proteins that result in the establishment of viral replication factories;(2) characterisation of the mechanisms employed by tetraviruses to regulate expression of their gene products and the role these systems play in virus replication and (4) understanding the mechanisms of viral RNA packaging during virus particle assembly and the development of drug and gene-delivery technologies.
Microbial ecology and marine natural products research
This research forms part of a multidisciplinary programme (Chemistry, Marine Biology Geography and Microbiology) to study the role of the microbiota (focusing on bacteria and viruses) in driving the functioning of marine ecosystems. The research programme is built around the application of high throughput (pyro)sequencing technologies and metagenomics to characterise microbial biodiversity and metabolic activity in aquatic ecosystems. Research projects include investigating (1) the diversity of microbial symbionts associated with marine sponges and other invertebrates (2) isolation and characterization of bioactive secondary metabolites and (3) exploring the pharmaceutical potential of selected bioactive small molecules.
1) Soil microbial ecology in Western Dornning Maud Land (Antarctica)
Microbes are critical to soil ecological functioning and this is particularly true in Antarctica where in many instances microbes are the sole soil biota present. It is generally accepted that due to the extreme abiotic conditions in Antarctica, the trophic component of ecosystems is constrained and in many instances is limited to microbial biota. Despite the harsh environment, molecular studies have revealed surprisingly high bacterial diversity profiles in Antarctic soils. Most of these studies are of soils from the McMurdo Dry Valleys in southern Victoria Land or on the Antarctic Peninsula. The only molecular based bacterial study on soil microorganisms done to date on the eastern Antarctic was carried out at Schirmacher Oasis where they used denaturing gradient electrophoresis to assess diversity profiles and sequenced a limited (i.e. 79) number of bands in order to identify the dominant microbes present (Teo & Wong 2014). Using quantitative analysis of distribution data in combination with expert-defined bioregions, Terauds et al. (2012) generated a map of Antarctica delineating several Antarctic Conservation Biogeographic regions. From this analysis, nunataks in the Western Dronning Maud Land form a biogeographic region unique to the rest of Antarctica (Terauds et al., 2012). Analysis of the microbial community in soils from Dronning Maud Land thus needs to be addressed in order to provide a holistic depiction of the distribution of microbes in the Antarctic continent. This study aims to fill this knowledge gap and to correlate diversity patterns to geographical location and/or abiotic factors.
2) Anthropogenic impacts in Antarctica
Sensitive Antarctic ecosystems are under threat from two major sources, namely global climate change and direct human impacts. Of these two, the extent and implications of human anthropogenic impacts have not being clearly ascertained and as a result, the necessary regulatory mechanisms cannot be put in place in order to protect Antarctic ecosystems.
While wastes are an obvious source of pollution in Antarctica, the mere presence of humans may present an alternative input of non-indigenous bacteria (albeit at a much reduced degree). The surface of the human skin is typically home to a natural assemblage of over a trillion microorganisms which are continuously released into the environment via skin sloughing, hair loss, coughing, sneezing, etc. While the number of human symbiotic bacteria released into the environment is likely to be somewhat lower in Antarctica (due to the several layers of clothes worn to combat the low temperatures) the number of non-indigenous bacteria entering the Antarctic system is likely to remain substantial.
The majority of the non-indigenous microorganism seeded into the Antarctic environment are mesophilic (grow in temperate conditions) and are unlikely to survive the extreme Antarctic environment but they could significantly contribute to the available pool of DNA which may be incorporated into the genomes of indigenous bacteria via horizontal gene transfer. Horizontal gene transfer is widespread among bacteria and while this phenomenon is well established in bacteria from a wide variety of environments, due to limited research, very few reports of gene transfer in cold environments have been documented.
While the potential negative impacts of non-indigenous bacteria/DNA into the Antarctic environment have been highlighted, minimal research has been carried out on the extent to which these bacteria impact the natural microbiota, the location of substantially impacted areas or the long term viability and /or effects of the non-indigenous bacteria in Antarctica. These questions need to be addressed in order for adequate regulatory protocols to be implemented.
(1) The Molecular Nose
While at the University of Glasgow and Aston University, I worked on the Molecular Nose Project. My research involved the design and development of a platform technology to track molecular signalling within mammalian cells and I applied this system to better understand the pathways that were affected in human cancers. This research has resulted in the publication of four articles to date (Jiwaji et al. 2010 BMC Molecular Biology 11:103; Reboud et al. 2012 PNAS 109:15162; Jiwaji et al. 2012 PLoS ONE 7(11): e50521 and Jiwaji et al. 2014 PLoS ONE 9(6): e99458).
The aim of my current research project is to apply the Molecular Nose sensor platform that detects shifts in transcriptional activity and utilizes a library of plasmid constructs, each of which encodes a transcription factor binding site (TFBS) linked to a unique reporter (UR). The Molecular Nose sensor platform currently encodes over 200 different TFBS-UR constructs each encoding TFBS sequences reported in published journal articles or TF databases (Messeguer et al. 2002 Bioinformatics 18:333; Farre et al. 2003 Nucleic Acids Res 31:3651; Matys et al. 2006 Nucleic Acids Res 34 (Database issue):D108). The output of this assay system results in the identification of TFs in the cell that are affected by treatment with the drug of interest and in doing so highlights which cellular signalling pathways have been activated giving an indication of bioactivity and specificity as well as the mechanism of action. This platform will be used to first, test the commercially available anti-breast cancer compounds to further develop the sensor platform and to define the baseline of the assay system. Thereafter the research will shift to the analysis of new lead compounds and compare them to the available drugs. This research will provide information on bioactivity and efficacy as well as specificity.
(2) Scaffold proteins
Scaffold proteins bring together proteins that need to be in proximity for signal transduction, and so enhance signal cascades. One of these scaffold proteins is the Connector enhancer of KSR (CNK) that has recently been described as a ‘super-scaffold’. CNK is known to be involved in the MAPK signalling pathway and dysfunction of this pathway is responsible for a number of diseases, including cancer. CNK is also involved in the NF-κB pathway but its role in this pathway is poorly understood; the NF-κB pathway is involved in the expression of genes that regulate essential cell processes including growth, proliferation and apoptosis.
The aim of this research project is to study the effect of the CNK protein on the NF-κB pathway. The NF-κB pathway will be activated by the addition of chemicals including phorbol 12-myristate 13-acetate (TPA) and tumour necrosis factor-alpha (TNF-α). The effect of the levels of CNK on the activity of the canonical (p50, RelA) and non-canonical (p52, RelB) NF-κB pathways in response to these stimuli will be studied. A better understanding of the role of CNK in the NF-κB pathway will allow us to better understand the numerous functions of the scaffold protein CNK in the cell.
Last Modified: Fri, 11 Dec 2015 14:58:55 SAST