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Epithelial calcium and mitochondrial signalling in the host response to fungal peptide toxins.


   Dental & Health Sciences Research

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  Dr Jonathan P Richardson, Dr J Naglik  No more applications being accepted  Funded PhD Project (UK Students Only)

About the Project

Epithelial cells are the first point of contact between the host and pathogenic microbes. During mucosal infection, the fungal pathogen Candida albicans secretes candidalysin, a peptide toxin that induces epithelial damage, calcium influx and mitochondrial dysfunction, which consequently affect cellular metabolism, immune responses, and ultimately cell death. Currently, the mechanisms by which candidalysin induces calcium influx and mitochondrial dysfunction is unknown.

This project aims to determine how candidalysin exerts its cellular effects via calcium and mitochondrial signalling. Year 1-2 in vitro studies will focus on using calcium channel inhibitors, RNA interference and CRISPR deletion to identify which calcium channels drive calcium influx/signalling by candidalysin. Mitochondrial activity will also be assessed using Seahorse analysis to determine whether calcium influx/signalling is a key driver of mitochondrial dysregulation, or an independent pathway induced by candidalysin. As candidalysin may also induce DNA release from mitochondria, the role of the cGAS-STING pathway in downstream immune activation will also be determined. Moreover, a potential relationship between calcium overload, mitochondrial permeability transition and candidalysin-induced cell necrosis will be investigated. Utilisation of candidalysin-deficient Candida strains will confirm the role of candidalysin in driving these cellular responses. In Year 3, the importance of calcium signalling and mitochondrial function in Candida infections will be confirmed in vivo using chemical inhibitors and relevant knockout mouse models.

This project will combine molecular/cellular biology, mammalian/fungal biology, host-pathogen interaction, immunology, and in vitro/in vivo infection models to determine how candidalysin drives cellular effects through calcium and mitochondrial signalling.

Research training (highlight skills candidates will develop or enhance)

·        Tissue culture.

·        Fungal culture.

·        In vitro/in vivo infection models.

·        Cellular assays (calcium influx, mitochondrial fitness, siRNA/chemical inhibition of signalling/CRISPR, immune activation, cell death).

·        Writing skills.

·        Presentation skills.

·        Data analysis and interpretation.

·        Teamwork skills.

·        Time management/planning skills.

Person specification:

·        We are seeking enthusiastic candidates interested in medical mycology/host-pathogen interaction. Applicants should possess a minimum of an upper second-class Honours degree, master's degree, or equivalent in a relevant subject. Previous experience with tissue culture, investigation of mammalian signalling pathways, and fungal biology would be an advantage.

Other/additional information:

·        The work will be performed in the Centre for Host-Microbiome Interactions, located within the Faculty of Dentistry, Oral & Craniofacial Sciences, which scored 100% for Environment in the recent 2022 Research Excellence Framework exercise.

Stipend and/or bench fees (amount): Studentship will fund: Stipend - £18,062 per annum, Bench fees - £5,000 per annum, and Home tuition fees

Duration of award/project: 3 years.

Further comments on available funding: Faculty funded studentship

Eligibility

·        Home students only.

Mode of study

·        Full time.

Project duration

·        3 years duration, with 1 additional year to complete write-up (unfunded). 

For more information please visit the project page: Epithelial calcium and mitochondrial signalling in the host response to fungal peptide toxins. | Faculty of Dentistry, Oral & Craniofacial Sciences | King’s College London (kcl.ac.uk)


Funding Notes

Studentship will fund: Stipend - £18,062 per annum, Bench fees - £5,000 per annum, and Home tuition fees

How good is research at King’s College London in Allied Health Professions, Dentistry, Nursing and Pharmacy?


Research output data provided by the Research Excellence Framework (REF)

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