This project investigates immune cell–specific roles of TRPC3/6 Ca²⁺ channels in psoriasis. Combining genetic mouse lines and a well-established murine model of psoriasis-like skin inflammation, it aims to define how TRPC3/6 regulate immune cell activation and evaluate their therapeutic potential in psoriatic disease.
Project Details
Background:
Transient Receptor Potential Canonical (TRPC) channels are non-selective Ca²⁺-permeable cation channels that play key roles in cellular Ca²⁺ signaling. While TRPC channels are best known for their functions in the cardiovascular and nervous systems, increasing evidence indicates that they also regulate immune cell activation, differentiation, and inflammatory signaling1. Psoriasis is a chronic immune-mediated inflammatory skin disease driven by complex interactions between innate and adaptive immune cells, including macrophages, T cells, B cells, dendritic cells, and neutrophils. Although altered expression of TRPC6 has been reported in psoriatic lesions2, the functional relevance of TRPC3 and TRPC6 channels in immune cell regulation during psoriatic inflammation remains poorly understood. So far, only limited evidence suggests that pharmacological activation of TRPC6, such as with hyperforin3, has beneficial effects; however, the underlying mechanisms remain poorly understood.
Hypothesis and Objectives:
We hypothesize that TRPC3 and TRPC6 channels critically regulate immune cell–specific Ca²⁺ signaling pathways that shape the development and severity of psoriatic inflammation. The objective of this project is to define the role of TRPC3/6-dependent Ca²⁺ signaling in immune cell–driven psoriasis and to identify the immune cell populations most strongly affected by modulation of these channels. Furthermore, we aim to determine whether targeted pharmacological manipulation of TRPC3/6 represents a viable therapeutic strategy for controlling psoriatic disease progression.
Methodology:
The PhD student will investigate the contribution of TRPC3 and TRPC6 channels to psoriatic inflammation using genetic mouse models and established pharmacological modulators. Preliminary data from our group already indicate altered immune cell composition in the spleen of TRPC3/6-deficient mice, with pronounced changes in macrophage, T cell, and B cell populations, supporting a systemic role of TRPC3/6 in immune regulation.
Psoriatic inflammation will be induced using the imiquimod (IMQ)-induced mouse model, a well-established in vivo model that mimics key pathological features of human psoriasis. Disease severity will be assessed using a PASI-like scoring system based on erythema, scaling, and skin thickening, complemented by histological analysis of epidermal thickness, hyperkeratosis, and epidermal differentiation.
Infiltrating immune cell populations in the skin—including macrophages, T cells, B cells, antigen-presenting cells, plasmacytoid dendritic cells, and neutrophils—will be characterized by immunohistochemistry and flow cytometry. Expression of inflammatory mediators, particularly components of the IL-23/IL-17 axis, will be quantified by qPCR in skin tissue. In parallel, immune cell composition and activation in spleen and lymph nodes will be analyzed to assess systemic immune alterations.
Based on these findings, immune cell subsets most strongly regulated by TRPC3/6 will be identified and subjected to targeted functional analyses, including Ca²⁺ influx measurements, activation marker expression, proliferation, and cytokine production. Finally, the therapeutic potential of established TRPC3/6 activators and inhibitors will be evaluated in vivo to assess their impact on psoriatic inflammation.
References
1. Wenning AS et al. (2011) TRP expression pattern and the functional importance of TRPC3 in primary human T-cells Biochim Biophys Acta Mol Cell Res 1813(3): 412–423
2. Leuner K et al. (2011) Reduced TRPC channel expression in psoriatic keratinocytes is associated with impaired differentiation and enhanced proliferation PLoS One 6(2): e14716
3. Zhang S et al. (2021) Hyperforin ameliorates imiquimod-induced psoriasis-like murine skin inflammation by modulating IL-17A-producing γδ T cells Front Immunol 12: 635076
People Involved
Primary supervisor: Sanja Curcic