Deciphering the mechanistic underpins of the inflammation-to-proliferation phase transition in human skin wound healing

Grantee: Ning Xu Landén, Associate Professor, Karolinska Institutet

Amount: DKK 4,164,510

Grant category: Research grants in open competition

Year: 2022

Geography: Sweden

Ning Xu Landén’s project seeks to improve wound healing by identifying key regulators of cellular transition from inflammation to proliferation, a cardinal event during normal skin wound healing which is lacking in chronic wounds.

Ning and her team will approach this by mapping the spatiotemporal changes, both genetic, molecular and cellular, happening during the healing of acute wounds. Using this mapping, she and her team will then aim to identify the core genetic changes and intercellular crosstalk which regulates the inflammation to proliferation transition. Once identified, these changes and intercellular crosstalk will be characterized in more detail.

The ultimate goal is to identify the “master” regulators of inflammation-to-proliferation transition in order to improve and accelerate wound healing and thus minimize the risk of development of chronic wounds.

If successful, this project could pave the way for a novel approach to wound healing which may also eventually reduce subsequent scarring.

New therapy and diagnostics of psoriasis vulgaris and psoriatic arthritis based on new animal models

Grantee: Rikard Holmdahl, Professor, Karolinska Institutet

Amount: DKK 3,622,500

Grant category: Research grants in open competition

Year: 2022

Geography: Sweden

Rikard Holmdahl and his team have discovered that mannan, a large natural sugar molecule found in yeast and plant cell walls, can induce a psoriasis-like condition in mice which strongly resembles human disease in terms of both genetics and clinical presentation.

The aim of Rikard’s research is to investigate the potential of this animal model to improve our understanding of disease mechanisms, predict disease progression and potentially treat psoriasis and psoriatic arthritis by modifying the sugar structure of mannan – hereby increasing the cellular level of reactive oxygen species which appears to be protective against disease development and progression.

In addition, Rikard’s team aims to identify new diagnostic (auto-)antibodies, found both in the mannan-induced psoriasis (MIP) mouse model and in a cohort of psoriatic arthritis patients, to improve early diagnosis and hence improve intervention.

If successful, the results could provide a new and more exact tool to further investigate what causes psoriasis and psoriasis arthritis, while at the same time potentially improving the efficiency of early diagnosis and subsequent treatment.

Protein aggregation in host defense and skin inflammation

Grantee: Artur Schmidtchen, Professor, Dermatology and Venereology, Department of Clinical Sciences, Lund University

Amount: DKK 2,100,000

Grant category: Research grants in open competition

Year: 2020

Geography: Sweden

The primary goal of this project is to identify and characterize the ‘aggregatome’, which describes the complete and complex network of proteins that are involved in the specific mechanism where the body – via its immune system – protects itself e.g. from bacteria. Subsequently, the project will explore and define the roles of the ‘aggregatome’ in inflammatory skin diseases.

The ultimate goal is to obtain new and deeper understanding of diseases affected by protein aggregation and potentially identify biomarkers of diagnostic significance.

Deciphering the Role of Non-Coding RNAs in Epidermal Carcinogenesis

Grantee: Andor Pivarcsi, Senior lecturer/Associate Professor, Department of Medical Biochemistry and Microbiology (IMBIM), Uppsala Universitet, Uppsala

Amount: DKK 4,164,300

Grant category: Research grants in open competition

Year: 2020

Geography: Sweden

The goal of this project is to investigate the potential role of long non-coding RNAs (lncRNAs, RNA molecules, which do not function through coding for protein, but by regulating other genes) in the development of the most common form of skin cancer with metastatic potential – Squamous Cell Carcinoma (SCC). Such RNAs are known to be key regulators of multiple cellular functions, tissue development and homeostasis, but their role in SCC is not clear. Andor Pivarcsi and his team have identified a group of long non-coding RNAs that have altered expression in this disease. As these lncRNAs may prove to be key players both in the development of cutaneous cancers and in the maintenance of normal skin homeostasis, they now want to investigate their function.

Andor Pivarcsi and his team will do so by defining the role and mechanism of action of selected lncRNAs by a combination of methods, including inhibiting them with anti-sense oligonucleotides, that will effectively prevent their association with natural binding partners. The results will improve our understanding of long non-coding RNAs in cutaneous malignancies and may pave the way towards improved antisense oligonucleotide-based skin cancer therapy.

Andor Pivarcsi is a former LEO Foundation Silver Award Winner (2010).

Molecular body map of human skin: the key for understanding human skin diseases

Grantee: Maria Kasper, Principal Investigator, Karolinska Institutet, Stockholm

Amount: DKK 3,949,807

Grant category: Research grants in open competition

Year: 2019

Geography: Sweden

Skin is the largest human organ and contains an intricate variety of cell types that assure tissue architecture and proper skin function, such as thermoregulation and hair growth.

An imbalance of cell types and/or molecular signalling often results in disease. Across the body, skin composition differs in thickness, hair growth, sebaceous and sweat gland density, microbiota exposure and disease susceptibility.

However, a molecular understanding of how cell types and genetic programs vary with skin regions, and molecular alterations in disease, is currently lacking.

Previously, my lab pioneered the use of single-cell RNA-seq (scRNA-seq) in mouse skin by generating a comprehensive molecular and spatial atlas of epithelial and mesenchymal cells during hair growth and rest (Joost et al. 2016; Joost et al. 2019). Building upon our expertise, we will molecularly dissect human skin, initially through a body map that spans various body sites of healthy donors, to identify cell types and sub types in human skin and also to investigate important cell type differences and alterations compared to mouse skin. Subsequently, the body map will be the foundation for molecular analyses of skin diseases, including immune-triggered psoriasis.

A carefully constructed and annotated human skin atlas, with spatial and molecular precision, would have enormous value for the scientific community and propel our molecular understanding of skin in health and disease.