Development of predictive psoriasis response endotypes using single cell transcriptomics in ustekinumab responders versus non-responders
Grantee: Kevin Cooper, Professor, University Hospitals Cleveland Medical Center
Amount: DKK 3,653,532
Grant category: Research Grants in open competition
Year: 2021
Geography: USA
Among the biological treatments approved for the treatment of psoriasis, is ustekinumab, which is a monoclonal antibody targeting the shared p40 subunit of two cytokines, IL12 and IL23.
This project aims to improve psoriasis treatment by understanding why some psoriasis patients respond well to treatment with ustekinumab (responders) and others do not (non-responders). Interestingly, some non-responders to ustekinumab still respond well to inhibition of the IL23 pathway alone via the unique p19 subunit.
The pattern of differentially expressed genes among responders and non-responders may enable prediction of which intervention will be most beneficial for the individual patient. The plan is to compare single-cell transcriptomic analyses from both responders and non-responders to identify treatment response-linked gene expression patterns, so-called ‘endotypes’.
One size does not fit all for these biological therapeutics, and the goal is for the research to contribute to the development of a ‘companion diagnostic’, which is a diagnostic test used as a companion to a therapeutic drug to determine its applicability to a specific person, and thereby to personalized medicine in psoriasis.
Melanocyte stem cell lineage determination and plasticity
Grantee: Deborah Lang, Associate Professor, Boston University School of Medicine
Amount: DKK 3,583,404
Grant category: Research Grants in open competition
Year: 2021
Geography: USA
Melanocytes are pigment-producing skin cells. They serve as an excellent model for stem cell research because they are easily obtainable from the skin and have the potential to be modified into other types of cells. The aims of this project are to define molecular events that promote stem cell maintenance and to test if melanocyte stem cells can be transformed into other cell types (such as nerves).
Deborah Lang has created a unique transgenic mouse model that fluorescently marks melanocyte stem cells. This model is an innovative and powerful tool to visualize and isolate pure stem cells without contaminating non-stem cells. The Lang lab, along with Andrey Sharov and other collaborators at Boston University, will investigate gene expression in the stem cells, and how these stem cells change into pigment-producing melanocytes. Further, the team will test the ability of the melanocyte stem cells to turn in to other cells, such as neurons and neuron-like cells.
This project will provide new insights into melanocyte stem cell function and flexibility to become other cell types. The potential long-term impact of this project is that it will provide insight on normal melanocyte function, melanocyte dysfunction and pathology, and stem cell therapy.
Positional Information and Repair of Skin Injury
Grantee: Peter Reddien, Professor, Whitehead Institute, Cambridge
Amount: DKK 2,498,235
Grant category: Research Grants in open competition
Year: 2021
Geography: USA
The project aims to investigate if an untapped potential for true skin regeneration exists in vertebrates not known to have the capacity to regrow skin tissue. If indeed such capacity exists and if it can be reactivated it may be possible to regenerate fully functional skin without any scarring.
Peter Reddien and his team at Whitehead Institute will look at the so-called “regional identity” of new cells which is central to regeneration in many animals capable of regeneration. They will use sophisticated techniques like single-cell RNA sequencing and spatial transcriptomics to compare factors and signaling pathways central to development in skin. Mouse skin – a vertebrate not known to be able to regenerate – and skin from a special regenerative salamander (axolotl) are used as models.
Peter Reddien’s research project is a basic skin science project with a novel approach to understanding the skin’s potential for regeneration.
Immunomodulatory porous biomaterials for skin regeneration
Grantee: Philip Scumpia, Assistant Professor, University of California – Los Angeles, CA
Amount: DKK 3,885,333
Grant category: Research Grants in open competition
Year: 2021
Geography: USA
This project predicts in situ/local immunomodulatory biomaterials as a novel therapeutic approach to engineer regenerative wound healing and limit scarring.
Local tissue engineering represents a promising approach to regenerate tissue, however, immunologic barriers to restore tissue strength and function must be overcome. In previous studies, Philip Scumpia has shown that by simply inducing an adaptive immune response from a novel synthetic biomaterial that mimics the natural porosity and other characteristics of the skin, it is possible to provide the inductive signals to regenerate hair follicles and sebaceous glands in small murine cutaneous wounds.
In this project, it is proposed to identify the cells and the signals from the innate and adaptive immune system responsible for switching profibrotic signals in the wound environment to regenerative signals. This will be achieved by combining novel, pro-regenerative biomaterial formulations with loss-of-function studies of cells and factors of the immune system. Single-cell RNA-sequencing, multiplexed immunofluorescent microscopy, and bioinformatics analyses will be applied to directly assess biomaterial-to-cell and cell-to-cell interactions at the molecular level.
If successful, the project may help identify key players in regenerative wound healing, which would be of great importance.
Sodium intake and storage in the skin
Grantee: Katrina Abuabara, Associate Professor, University of California – San Francisco, CA
Amount: DKK 3,965,534
Grant category: Research Grants in open competition
Year: 2021
Geography: USA
The rapid increase in prevalence of AD suggests that environmental factors play an important role, but which environmental drivers are most important and the mechanism by which they impact AD is unclear. Large epidemiological studies suggest that changing diets are an important contributor. Dietary sodium intake warrants additional investigation because studies have shown high rates of sodium storage in the skin and that high sodium concentrations can trigger inflammatory responses involved in AD.
To study this, Katrina Abuabara will enroll 30 participants and employ a novel Magnetic Resonance Imaging (MRI) technique that has been shown to accurately quantify skin sodium concentration to examine whether a low-sodium diet can decrease skin sodium concentration and improve AD severity. The study presents a strong statistical analysis plan to identify key parameters for a future full-scale clinical trial.
If sodium restriction proves to be beneficial, it could lead to actionable impact on AD patients as a cost-effective, low-risk intervention that could be implemented in low resource settings.