Deciphering the mechanisms of sebaceous gland stem cell renewal and differentiation

Grantee: Catherin Niemann, Principal Investigator, University of Cologne

Amount: DKK 2,594,340

Grant category: Research Grants in open competition

Year: 2022

Geography: Germany

The aim of Catherin Niemann’s project is to understand the biologic events during sebaceous gland differentiation, tissue remodeling, and regeneration.

Sebaceous glands (SGs) are critical for the physiological balance and barrier function of mammalian skin. SG dysfunction is associated with a variety of skin diseases, including acne. Despite recent advances using mutant mouse models with SG defects, the main drivers of normal SG functions remain incompletely understood. Therefore, a better understanding of how SG physiology and sebum production (an oily mixture produced by sebocytes, cells of the sebaceous gland) are regulated, is a clinical necessity.

Using both in vivo and in vitro models, Catherin’s project will focus on the regulation of SG stem cells, which are the primary responders to stimuli at the interface with the tissue environment. In vivo, Catherin and her team will use a combination of genetic mouse models and high throughput technologies to identify key players controlling normal SG activity. In vitro, the team has developed a 3D cell culture model that will be modelled to mimic SG differentiation to uncover and validate the central mechanisms of SG regulation. This SG-organoid model will be especially beneficial to decipher the specific role of extra-cellular matrix components in SG physiology and to examine the interaction with other cell types, including immune cells, for their impact on SG cell differentiation and contribution to SG defects in disease settings.

The long-term goal of the project is to establish a platform for testing new therapeutic strategies for the treatment of SG disorders.

Stabilization of α-melanocyte stimulating hormone (α-MSH) for the therapy of dermatological diseases

Grantee: Michael Bader, Professor, Max-Delbrück-Center for Molecular Medicine

Amount: DKK 3,885,000

Grant category: Research Grants in open competition

Year: 2022

Geography: Germany

Michael Bader’s project aims to develop novel angiotensin-converting enzyme 2 (ACE2) inhibitors to be applied to the skin for treating inflammatory skin diseases.

Alpha-melanocyte-stimulating hormone (α-MSH) acting through its receptor, melanocortin 1 receptor (MC1R), is the most important regulator of melanogenesis (i.e., the production of melanin, the pigment of the skin) and also exerts significant anti-inflammatory actions in the skin. Therefore, MC1R may be a significant treatment target for inflammatory skin diseases and for prevention of melanoma, and several agonists are already clinically approved or currently being developed.

Michael and his group have discovered that ACE2 limits melanogenesis in mouse and human skin by degrading α-MSH. Thus, ACE2 inhibition in the skin may be a novel strategy for dermatological diseases by stabilizing α-MSH and thereby activating MC1R.

However, ACE2 is also a protective enzyme in the circulation limiting the actions of the blood pressure regulatory system, the renin-angiotensin system. Therefore, systemic inhibition of ACE2 may cause severe side-effects, making topical application of ACE2-inhibitors preferable.

Michael and his team have already tested a number of available ACE2-inhibiting compounds, but none were suitable for topical application “as-is”. In this project, they will chemically design variants of known ACE2 inhibitors to optimize for skin permeation and test them in a mouse model of vitiligo. If they are successful, these compounds can also be tested in other inflammatory skin diseases, such as acne and psoriasis, for melanoma prevention, and perhaps even for cosmetic applications, such as skin tanning and prevention of hair greying.

Towards a Cure of Genodermatoses: Intraepidermal Delivery of Gene Editing Tools Leveraging Smart Delivery Systems

Grantee: Sarah Hedtrich, Associate Professor, Charité Hospital Berlin

Amount: DKK 4,183,544

Grant category: Research Grants in open competition

Year: 2022

Geography: Germany

Sarah Hedtrich, who is also Associate Professor at the Faculty of Pharmaceutical Sciences of the University of British Columbia, leads this project focusing on developing novel ways to treat genetic skin diseases through intra-skin delivery methods.

Skin diseases caused by specific genetic defects (genodermatoses) are often rare but can be severe and even life threatening – like epidermolysis bullosa. To cure such diseases, the genetic errors which cause the diseases would need to be corrected. In recent years there have been major advances in targeted gene editing – not least with the CRISPR/Cas system which allows for both tissue- and cell-specific correction.

However, while the skin is readily accessible it has two features which impede such treatment: Firstly, the skin’s barrier function makes efficient delivery difficult, and secondly, as the skin is an epithelium with rapid turnover of the cells, a persistent cure involving gene editing must reach the stem cells which lie at the base of the epidermis, the outer layer of the skin.

Sarah and her team, with expertise in both dermatology, gene editing and topical drug delivery, aim to develop such a delivery system for gene correction treatments using microneedles and nanocapsules, and will investigate its efficiency in both human skin samples and bioengineered skin (disease) models.