Vanessa Hoang Quang

Research project: 

Hidradenitis suppurativa: a model of vulnerability

Affecting 1 to 4% of people, mainly young one and women, hidradenitis suppurativa (HS) is a chronic painful inflammatory skin disease. It specifically takes place in the intimate skin folds, such as armpits, groin and anogenital areas. Instead of a phenotypic heterogeneity, it’s believed that the vicious cycle begins with an initial perifollicular inflammation, due to keratinocyte dysregulation. It leads to formation of cysts which dilate and can be broken, releasing their content into the dermis. This event chronically triggers multiple inflammatory pathways and immune system, leading to sinus tract and scar formation in more severe cases. Currently, there is no effective and healing treatment, impacting dramatically the patient's quality of life, making it a vulnerable disability and having a big societal issue and cost.

Even though its physiopathological mechanisms are still poorly understood, HS is known to have a multifactorial origin and risk factors: genetics, smoking, gut and skin dysbiosis and obesity. In this PhD project, we are going to focus on two aspects of HS: the genetic factor and the hair follicles stem cells (HF-SCs). On the one hand, a positive family history is observed in 30-40% of the HS patients. Mutations are mainly detected in genes coding for secretase, a transmembrane multisubunit protease, which is involved in cell homeostasis through Notch pathway. Its inactivation induces an increase of keratinocyte proliferation and differentiation, accompanied by a pro-inflammatory profile. On the other hand, previous studies, including ours, have demonstrated the same observation with patients’ hair follicle stem cells, suggesting HS is a follicular disease. The goal of this project is to conceive a robust mouse model of the HS disease. We hypothesize that the inactivation of ????-secretase in HF-SCs affects their proliferative activity and differentiation potential and recapitulates, at least partly, the pathophysiology of HS. To achieve this study, 2 work packages will be performed. In WP1, we will perform detailed analysis of the mouse model (Krox20Cre, Ncstnflox/flox, Rosa26Tom). In WP2, we will use this mouse model for deciphering the role of environmental (pollution, obesity) factors as triggers promoting HS.

We will generate Krox20Cre, Ncstnflox/flox, Rosa26Tom mice. The goal is to simultaneously target ????-secretase deletion and constitutive expression of fluorescent reporter Tomato to HF-SC. Such a strategy should allow us to identify, purify and manipulate ????-secretase-/- HF-SCs and all their derivatives thanks to the expression of Tomato reporter. From those mouse models, we will evaluate, whether i) the ????-secretase loss is sufficient to trigger the pathogenesis, and ii) whether added environmental hits can trigger or accelerate or accentuate the HS lesion development. Our final aim is to create a new experimental model to have a better understanding of this disease by identifying new candidate genes and pathways, as well as new inflammatory biomarkers, yet undiscovered in human beings.