Dissection of mTOR signaling in the pathogenesis of psoriasis

• Applicant: Privatdozentin Dr. Claudia Bürger
• Subject Area: Dermatology
• Term: from 2014 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 261638619

In order to form a multilayered and functional epidermis, as the outermost shell of the body, keratinocytes underlie a tight regulation between cell division (proliferation) in the basal layer and ordered maturation (differentiation) into corneocytes. In inflammatory diseases such as psoriasis, this tightly controlled balance is disturbed. Increased cell division combined with impaired differentiation leads to the formation of red, scaly lesions. Although modern systemic therapeutics show promising results, there is still a need for topical therapies that can specifically influence these deregulated processes in the epidermisWe could previously show that the mTOR (mechanistic target of rapamycin) complex (mTORC1) is a central regulator of epidermal homeostasis. In keratinocytes of the basal layer, mTORC1 is active and contributes to the control of proliferation while blocking differentiation. When cells leave the proliferative compartment, mTORC1 is switched off and differentiation is enabled. Under inflammatory conditions, however, mTORC1 is constantly activated. This blocks ordered cell maturation, induces massive proliferation and ultimately results in the typical psoriatic skin changes.Currently it is not understood how mTORC1 is switched off, when cells leave the proliferative compartment and which effectors downstream of mTORC1 mediate the differentiation defects. Since in other tissues mTORC1 is negatively regulated by the Tuberous Sclerosis Complex (TSC), the activity of TSC in psoriatic skin will be analyzed first. Using CRISPR/Cas9-mediated genome editing, TSC2 will be knocked out in immortalized keratinocytes, which should lead to a constant high mTORC1 activity and potentially give the cells a psoriasis-like phenotype. In these cells, the influence of disturbed mTORC1 regulation on proliferation, differentiation and formation of the three-dimensional epidermis can be investigated in detail. These cells will be also used to study the downstream effectors of aberrant mTORC1 activity. Especially processes that are potentially involved in keratinocyte maturation and are shown to be deregulated in psoriasis, such as transcription by STAT3, translation of keratins and autophagy will be studied. In summary, the proposed project will elucidate mechanisms by which mTORC1, as a central signal integrator, regulates epidermal homeostasis. Insights into the deregulation of these processes will not only contribute to a better understanding of psoriasis pathogenesis, but also identify signaling molecules and mediators that are suitable as potential targets for topical therapies.

• DFG Programme: Research Grants