Dysregulation of gamma secretase in common acquired hidradenitis suppurativa

The National Institute of Allergy and Infectious Diseases awarded The Johns Hopkins University $271,574 on November 3, 2025, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to conduct research on gamma secretase dysregulation in acquired hidradenitis suppurativa.

The project, titled "Dysregulation of Gamma Secretase in Common Acquired Hidradenitis Suppurativa" (F30AI191436), investigates the molecular mechanisms underlying hidradenitis suppurativa, a chronic inflammatory skin disease characterized by debilitating lesions and scarring. The research defines the enzymatic activity of gamma secretase and regulation of nicastrin expression in hidradenitis suppurativa fibroblasts in response to exposure to plastic-associated endocrine disruptors. The project tests the hypothesis that acquired hidradenitis suppurativa phenocopies monogenic disease through shared loss of nicastrin and subsequent gamma secretase dysregulation. Performance occurs in Baltimore, Maryland, with work scheduled from the award date through May 14, 2028.

Abstract

Hidradenitis suppurativa (HS) is a chronic inflammatory disease that significantly reduces quality of life due to debilitating skin lesions and scarring. HS may be caused by a single gene mutation, most commonly in the nicastrin (ncstn) subunit of the γ-secretase (ΓS) protease complex, which regulates substrate access to ΓS. In a majority of patients with acquired HS, there is no identifiable mutation, yet they suffer an identical clinical phenotype to monogenic HS. While HS has historically been understood as a disease of keratinocytes, recent discoveries have identified dermal fibroblasts as important loci of inflammatory signaling in HS skin. Further, ncstn is decreased in dermal fibroblasts of acquired HS patients, which may drive aberrant immune signaling from these cells. These findings support the global hypothesis that acquired HS phenocopies monogenic HS due to shared loss of ncstn and subsequent ΓS dysregulation. However, the enzymatic activity of ΓS in HS patients, as well as the factors which drive ncstn loss, remain exciting areas of future discovery. Epidemiological studies suggest that cases of acquired HS have been increasing over the past 3 decades. Given well-characterized clinical data that HS only occurs post-puberty and improves with hormone-modifying medications, this increase is likely to be driven in part by an environmental factor. Additional data suggests that in acquired HS, both skin lesions and fibroblasts cultured EX vivo have high levels of plastic-associated endocrine disruptors (peds) compared to healthy controls and that ncstn protein expression in fibroblasts is decreased by exposure to physiologically relevant concentrations of peds. To address these questions, i plan to define the enzymatic activity of ΓS and regulation of ncstn expression in HS fibroblasts and in PED exposure. My preliminary analysis indicates that ΓS proteolytic activity is decreased in HS fibroblasts for a specific substrate, which may drive downstream inflammatory pathways. In this project, i will test the hypothesis that that ΓS kinetics and ncstn regulation in HS fibroblasts differ from healthy controls and that treatment of normal fibroblasts with peds will phenocopy HS. I will quantify ΓS activity using a förster resonance energy transfer (fret) assay and characterize changes in inflammatory cytokines using functional in vitro studies. In parallel, i will also characterize the regulation of ncstn protein expression and identify major regulatory networks in HS and PED exposure by analyzing chromatin accessibility and gene expression through single-cell atac and RNA sequencing. With these studies, i hope to define the role of ΓS activity and ncstn regulation in HS. Further, i aim to definitively clarify the role of peds in HS through rigorous studies. Understanding these relationships could have important implications for the treatment and management of HS and other diseases with ΓS dysfunction.