Studying biological variation in the environmental sensor and novel psoriasis drug target Aryl Hydrocarbon Receptor (AHR): expression, regulation and biomarker potential

Award details

Psoriasis is an immune-mediated, chronic inflammatory skin condition due to combination of genetic predisposition, environmental triggers, and dysregulated innate and adaptive immune responses [1]. The disease has a major impact on patient’s quality of life and pose a significant financial burden on the healthcare system. Recent progress in the identification of key cellular player and molecular pathways underpinning disease pathogenesis has led to the design and use of effective targeted therapies against key pro-inflammatory cytokines. Nevertheless, not all patients respond to the current treatment, suggesting that suggesting that additional molecular pathways can be targeted for therapeutic purposes.

Most of the recent innovations have been targeted to the moderate-to-severe patient population, while patients with mild-to-moderate disease, who makes up 80% of the psoriasis population, have not benefitted from these innovations. Therefore, an unmet clinical need exists for novel, safe, effective, and affordable therapies for patients with mild-to-moderate disease.

In contrast to the substantial progress in delineating the genetic and immunological landscape of psoriasis, the study of its environmental component is largely limited to epidemiological studies. Environmental factors account for 30% of psoriasis risk but their mechanistic role in disease etiopathogenesis is ill understood. Hence, the investigation of environmentally regulated pathways may offer novel opportunities to understand disease mechanisms, identify novel therapeutic targets in psoriasis and potentially provide a scientific rationale for the implementation of lifestyle prevention measure.

The AHR is a member of the PER-ARNT-SIM (PAS) domain family of ligand-activated transcriptional regulators acting as environmental sensors to direct homeostatic changes through modulation of gene expression [2]. AHR ligands include xenobiotic (e.g. dioxins) and physiological ligands, such as indole derivatives of tryptophan of dietary, light and microbial or host metabolism origin. AHR is expressed at barrier organs, such as the skin, where signals mediated by physiological ligands maintains barrier integrity and prevents excessive inflammation through direct and indirect transcriptional regulation of proinflammatory genes. Upon ligand binding, AHR translocates to the nucleus, complexes with its partner ARNT and binds the DNA on AHR Responsive Element, regulating gene expression. Target genes include cytochrome P450 (CYP) enzymes, such as CYP1A1, which provides a negative feedback metabolising AHR physiological ligands, and genes involved in keratinocytes differentiation. Earlier work by the Di Meglio Lab has put AHR under the spotlight in psoriasis, showing for the first time that AHR signalling constrains skin inflammation in psoriasis samples and disease models [3] and that that psoriasis patients display increased CYP1A1 enzymatic activity, suggesting an impairment of beneficial AHR signalling due to excessive ligand metabolism mediated by CYP1A1 [4]. Importantly, topical application of tapinarof, a bacterial metabolite and AHR ligand, has shown clinical efficacy in clinical trials for psoriasis and has been approved by the FDA [5]. Moreover, a recent meta-analysis of Genome wide association studies (GWAS)[6] has revealed a novel genetic association implicating the AHR locus, suggesting that variations in the AHR gene or its regulatory regions may contribute to an increased risk of developing psoriasis.

Thus, AHR is a critical regulator of cellular homeostasis in the skin and a desirable target for the control of skin inflammation. Currently, both the research focus and the targeting strategy mostly revolve around the ligand-mediated activation of AHR signalling. However, little is known about the transcriptional regulation of AHR in itself, and the expression profile of AHR in psoriasis remains controversial [7-9]. Both the literature and our own unpublished data suggest that AHR expression and transcriptional regulation are likely to be altered in psoriasis and there may be biological variation in healthy and diseased skin of individuals from different populations. Crucially, these findings may have important clinical implications. The current therapeutic strategy harnessing the anti-inflammatory effect of the AHR pathway in skin inflammation is aimed at promoting anti-inflammatory AHR signalling by supplying AHR ligands, such as tapinarof, which however require adequate expression of AHR to be effective. Therefore, a deep understanding of AHR expression and regulation in psoriasis is a necessary step to better tailor therapeutic interventions aimed at harnessing its anti-inflammatory effect.

The purpose of this studentship is to gain better insights into the genetic and immunological basis of AHR regulation of AHR in the skin of psoriasis patients and healthy controls of different ethnic groups and evaluate the clinical implications of these findings in the context of tapinarof treatment optimization.

The PhD student will be based at St John’s Institute of Dermatology which provides an ideal environment for psoriasis research, with an established network of immunologists, cell biologists, data analyst and academic dermatologists. The student will have access to state-of-the-art equipment and technologies to conduct this project and will be supported by mentorships schemes and training courses, tailored to their specific needs. The student will have two supervisors with complimentary expertise in immunology (Dr Di Meglio, >15 years of experience in psoriasis research and pioneering the field of AHR in psoriasis for >10 years) and clinical dermatology (Prof. Catherine Smith, > 20 years as consultant dermatologist, with profound expertise in psoriasis research and experienced PhD and MD Supervisor) and a successful collaborative history since 2013.

 

References

1. Di Meglio P et al. Cold Spring Harb Perspect Med. 2014;4(8) 2. Stockinger, B., et al., Annu Rev Immunol, 2014. 32: 3. Di Meglio, P., et al., Immunity, 2014. 40(6): p. 989-1001.4. Kyoreva, M., et al., J Invest Dermatol, 2021.141. 5.Lebwohl, M., et al., N Engl J Med. 2021;385(24):2219-29. 6. Dand N et al. medRxiv [Preprint]. 2023 Oct 5:2023.10.04.23296543. 7. Wanner, R., et al., Biochim Biophys Acta, 1996. 1317. 8. Kim, H.O., et al., Exp Dermatol, 2014. 23. 9. Kim, H.R., et al., Int J Mol Sci, 2020.

Award value

The studentship is fully funded for three years. This includes home tuition fees, stipend, and project consumables.

Stipend: Students will receive a tax-free stipend at the UKRI rate of (£22,780 for AY 2024/25) per year as a living allowance.

Eligibility criteria

Minimum Upper Second (above 60%) BSc degree in a Life Sciences subject e.g. biomedical sciences or pharmacology or an MSc in a relevant area.

English Language Requirements:

Band D

Open to Home (UK and EU nationals who have settled or pre-settled status in UK) fee status applicants only.

Application process

Start date: 1st June 2025 Interview date: from 10th April 2025 Please submit an application for the Basic and Medical Bioscience Research MPhil/PhD (Full-time) using the KCL online application form. Before completing the application click here for information about the programme, requirements and details of what documentation and information needs to be included in your application. Please include in your application: · Details of previous employment where applicable · A 500-word personal statement outlining your motivation for undertaking postgraduate research should be uploaded to the Supporting statement section. · References: two supporting references are required with at least one academic. Professional references will be accepted if you have completed your qualifications over five years ago. The prospective supervisors must not be given as referees. Applicant must ensure that their chosen referees are made aware of the requirement to submit the reference before the application deadline. In the application form under ‘Funding information’: Please select option 5 ‘I am applying for a funding award or scholarship administered by King’s College London’ and under ‘Award Scheme Code or Name’ add 2025/BMBS/06. Failing to include this code might result in you not being considered for this funding. It is highly recommended to informally approach Dr. Paola DiMeglio before making an application. For administrative and application process enquiries please contact BMBS PGR.