This PhD opportunity is being offered as part of the LSTM and Lancaster University Doctoral Training Partnership. Find out more about the studentships and how to apply.
| Abstract | Snakebite is a medical emergency causing rapid onset of both local tissue-destructive and potentially lethal systemic haemorrhagic and neurotoxic pathologies. Snakebite primarily afflicts remote, impoverished, rural farming communities in regions with weak medical and ambulatory infrastructures. It annually kills approximately 138,000 people and 400,000 surviving victims suffer a substantially reduced quality of life due to the multiple effects of permanent physical and psychological disabilities. Current snakebite therapeutics (serotherapies known as antivenoms) have several deficiencies associated with them, including limited cross-snake species efficacy, poor safety, high cost, and variable quality, the latter largely due to a lack of robust clinical evaluation. Because snakebite is a neglected tropical disease and a medical emergency, many antivenoms have been approved for human use based predominately on preclinical evaluation in small animal models. Unfortunately such models to not accurately reflect human envenoming given substantial differences between route of venom delivery (often given intravenously preclinically, which rarely occurs in patients) and therapeutic delivery (often given as co-incubated, co-delivery with venom, which never happens in patients), which ultimately makes predictions of efficacy and appropriate levels of human therapeutic dosing challenging. In this project, we will seek to redress these limitations in snakebite preclinical research by developing appropriate in vitro and in vivo models that more accurately model envenoming pathology and will enable therapeutic decision making via the delivery of quantifiable outcomes that enable therapeutic efficacy readouts and dose predictions. In two parallel research arms we will seek to further develop: 1) a pilot microdosing envenoming animal model, in which lowly toxic doses of venom are optimised, delivered via a dosing route that reflects real world envenoming, and biomarkers of snakebite pathology identified and validated to use as experimental outcomes. This model will seek to reduce the severity of envenoming suffered by experimental animals and instead incorporate different types of pathology, with early measures of coagulopathy, haemorrhage, neurotoxic paralysis and local tissue damage identified and validated as a refinement of animal research. 2) organ on a chip models to model envenoming pathology in an in vitro environment. Using microfluidic technology, we will develop tissue-specific models of pathology (e.g. heart, kidney, lungs, skin) and define the consequences of envenoming to different tissue types, with comparisons with tissue harvested from preclinical research models used to evaluate their potential as replacement models for in vivo research. Following model development and validation, we will then use a variety of different therapeutic molecules currently under study for treating snakebite (monoclonal antibodies, oral drugs, and conventional antivenoms) to evaluate efficacy at preventing snakebite pathology. This project is anticipated to result in the development of new, more ethically appropriate and predictive models of snakebite envenoming that will aid the future evaluation of snakebite therapeutics. The successful applicant will join the dynamic and well-funded team at LSTM’s Centre for Snakebite Research and Interventions (CSRI). |
| Where does this project lie in the translational pathway? | T1 - Basic Research |
| Methodological Aspects |
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| Expected Outputs | Technical Outputs:
Institutional Impact:
Student Career Enhancement:
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| Training Opportunities | The student will be exposed to a wide variety of research training opportunities, as they will join a well-funded, multi-disciplinary and dynamic team of post docs, students and technicians. Thus, they will have an opportunity to acquire additional clinical and lab skill sets to those described above. In terms of career development, the student will receive ample and diverse training commensurate with developing an appropriately competitive CV for acquiring funding to support their career after the PhD. |
| Skills Required | A biomedical science or immunology or cell biology background would be desirable. Critical thinking skills, a passion for research, and a meticulous nature, are highly sought after |
| Subject Areas | Snakebite; Neglected tropical diseases |
| Key Publications associated with this project |
https://www.mdpi.com/2072-6651/12/9/528 https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0008579 https://f1000research.com/articles/13-192/v1 |