Regulatory Function of Dermal Adipocytes in Skin and Systemic Energy Homeostasis
Grantee: Nils Færgeman, Professor, University of Southern Denmark
Amount: DKK 2,336,250
Grant category: Research Grants in open competition
Year: 2022
Geography: Denmark
Nils Færgeman’s proposal investigates the role of acyl-CoA binding protein (ACBP) in regulating dermal white adipose tissue function in the skin.
Dermal white adipose tissue (dWAT) is a distinct type of fat depot located under the reticular dermis (the deepest layer of the dermis) and comprises a special layer of the skin. Compared to other well-defined fat depots, dWAT shows a very high degree of plasticity, and can rapidly and locally expand and reduce its volume in response to various stimuli.
Via lipolysis (an enzymatic process that releases free fatty acids from triglycerides in fat depots) dermal white adipocytes (fat cells) release fatty acids into the extracellular space, which for example can regulate production of extracellular matrix in dermal fibroblasts and differentiation of keratinocytes.
Recently, Nils and colleagues have demonstrated that acyl-CoA binding protein plays a fundamental role in lipid metabolism in the skin and is indispensable for its barrier function. Given that ACBP is required for differentiation of white adipocytes and given its high expression in the skin, the hypothesis behind this project is that ACBP plays a critical role in dermal adipose tissue by serving as a key regulator and driver of intracellular fatty acid metabolism.
The group will use state-of-the-art lipidomics (global analyses of lipid composition and abundance) and genomics technologies and a series of novel mouse models, to clarify the role of ACBP in dWAT functions in the skin and to define the role of dWAT in systemic energy metabolism.
Treatment of ichthyosis with enzyme replacement therapy
Grantee: Lotte K. Vogel , Associate Professor, University of Copenhagen
Amount: DKK 3,000,900
Grant category: Research Grants in open competition
Year: 2022
Geography: Denmark
This project led by Lotte K. Vogel aims to elucidate the role of the protease matriptase (an enzyme that cleaves proteins) in a variant of Ichthyosis, a common skin disease that causes “fish-scale” like skin with poor treatment options.
The molecular mechanisms behind ichthyosis are not understood, but variations in several genes may cause ichthyosis. Variants of the ST14 gene, which encodes the serine protease matriptase, lead to a type of ichthyosis called Autosomal Recessive Congenital Ichthyosis 11 (ARCI11). The prevalence of ARCI11 is elusive at present.
Lotte and her team’s preliminary data show that ARCI11-related matriptase variants are unable to activate a certain substrate (a protease on its own), suggesting that ARCI11 is caused by a lack of activation of this protease. Results from the group also suggest that inactivation of a certain enzyme cascade leads to Ichthyosis. Surprisingly, for several enzymes in this cascade both the zymogen form and the activated form of the enzyme exhibit proteolytic activity.
In this project, Lotte aims to investigate the importance of matriptase in ARCI11 through a three-pronged approach: (1) by elucidating whether a protease located downstream of matriptase in the same pathway can be activated by an appropriate soluble enzyme which is suitable for topical application to the skin. (2) by elucidating whether ARCI11 is caused by a difference in substrate preferences between the zymogen form and the activated form of these enzymes and (3) by systematically screening for genetic variants of matriptase causing ARCI11 and estimating their frequency in the population. The genetic material to do a more systematic search for ARCI11-causing variants of matriptase and estimate their frequency Is already available.
If successful, Lotte’s project will make a solid and original contribution to the understanding of ichthyosis that may lead to improved treatment options.
Structure and modulation of the integrin receptor αMβ2 in relation to SLE
Grantee: Gregers Andersen, Professor, Aarhus University
Amount: DKK 1,713,040
Grant category: Research Grants in open competition
Year: 2022
Geography: Denmark
Gregers Andersen’s project aims to understand the role of disease-related mutations of a central inflammation-regulating protein on immune cells in systemic lupus erythematosus (SLE).
Systemic lupus erythematosus is a severe autoimmune disease in which our immune system is erroneously activated. This leads to inflammation that may destroy tissue, such as the kidney. SLE often manifests itself with visible skin rashes that are difficult to treat and debilitating for the patient. Current options for treatment of SLE are insufficient and still rely heavily on steroids as the mainstay of treatment.
Both environmental and genetic factors contribute to SLE pathogenesis. The strongest association between SLE and the information encoded in our genetic material is observed for a specific mutation in a gene called ITGAM. This gene codes for a protein called αMβ2 located at the surface of our immune cells. When the αMβ2 protein recognizes specific proteins on other cells, the immune cell contributes to dampening inflammation. When the ITGAM gene is mutated, the immune cells are less efficient in suppressing inflammation.
Using the most powerful microscope available, Gregers’ research project will investigate in atomic detail how the mutation interferes with the normal function of the αMβ2 protein. Furthermore, the effects of a new antibody capable of increasing the activity of αMβ2 will be exhaustively investigated. Experiments comparing the effects of this antibody on immune cells from healthy and SLE individuals will be central in deciding whether the antibody is a candidate for a new type of therapeutic agent.
Deliniating the functional role of ERAP2 and HLA-C in the pathogenesis of psoriasis
Grantee: Claus Johansen, Associate Professor, Aarhus University
Amount: DKK 3,230,325
Grant category: Research Grants in open competition
Year: 2022
Geography: Denmark
Claus Johansen’s project investigates the role of the protein ERAP2 in the pathogenesis of psoriasis.
Psoriasis is considered an autoimmune disease – i.e., a disease in which the T-cells of the immune system attack and destroy the body’s own cells by error. During an exposure to external factors (peptides, bacteria etc) a system of specialized cells engulfs, digests, and presents peptide fragments (antigens) of these external factors on their surface to the body’s immune cells – usually cytotoxic CD8+ T-cells – which, once activated, then surveil, identify, and destroy foreign elements containing that specific peptide or peptides with very similar overall structure. The peptides are presented by a specific receptor, called the human leukocyte antigen (HLA) receptor and it is well-known that a particular subtype of this receptor, the HLA-C receptor is dominant in psoriatic patients – still, concrete disease-specific self-antigens have not yet been identified. Recent results have indicated that a protein, ERAP2, which facilitates the association of antigen peptides to HLA receptors may have a role to play in the erroneous recognition of self-antigens in autoimmune diseases like psoriasis. Claus and his team aim to clarify the role of this protein in the current proposal.
If successful, their project may help shed further light on the autoimmune characteristics of psoriasis – and eventually help guide new treatment approaches.
Control of cutaneous immune responses by T follicular regulatory cells in systemic autoimmunity
Grantee: Søren Degn, Associate Professor, Aarhus University
Amount: DKK 2,795,064
Grant category: Research Grants in open competition
Year: 2022
Geography: Denmark
This project, led by Søren Degn, aims to investigate the role of a newly discovered immune cell, the T follicular regulatory cell (Tfr), in controlling systemic autoimmunity.
Søren Degn and his team have discovered that Tfrs are able to maintain tolerance in the skin even in the face of systemic inflammation, which in that case appear to be reversible, but also that if Tfr control in the skin fails, the systemic inflammation becomes irreversible and chronic.
Using a mouse model where Tfrs are selectively deleted, Søren and his team will investigate immune responses and identify which specific self-antigens are targeted when the tolerance maintained by the Tfrs is lost.
Chemical compounds that impede the pathogenic effects of Staphylococcus aureus in atopic dermatitis
Grantee: Tim Tolker-Nielsen, Professor, University of Copenhagen
Amount: DKK 3,236,161
Grant category: Research Grants in open competition
Year: 2022
Geography: Denmark
The project by Tim Tolker-Nielsen aims to identify novel chemical compounds as potential drug leads for treating bacterial involvement in atopic dermatitis. The present project builds on findings from another LEO Foundation grant, which discovered a central factor, Sbi, responsible for the virulence (the ability to cause disease) of the bacteria Staphylococcus aureus in atopic dermatitis flares. As this factor appears to be unique to that bacterium it can be targeted with minimal impact expected on beneficial commensal (i.e. non-pathogenic) bacteria. Tim and his team will utilize existing libraries of chemical compounds to screen for lead candidates that can prevent the production of Sbi and which may be developed into a future treatment for atopic dermatitis flares.