Inhibitors of ERAP1 or ERAP2 to modulate antigen processing towards new psoriasis treatment
Grantee: Rebecca Deprez-Poulain, Professor, Institut Pasteur de Lille
Amount: DKK 3,190,714
Grant category: Research Grants in open competition
Year: 2024
Geography: France
A novel model to study aging of skin immunity
Grantee: Nicolas Manel, Research Director, Institute Curie
Amount: DKK 2,723,700
Grant category: Research Grants in open competition
Year: 2024
Geography: France
Nicolas Manel’s project explores the mechanisms of skin aging and immunity dysfunction, with a focus on establishing a novel model for investigating the role of the nuclear envelope in skin aging.
Genome instability is considered a central mechanism of aging. The nuclear envelope is essential for genome stability. Nicolas Manel’s laboratory recently reported that in mice deficient for a protein of the nuclear envelope in the immune system, alveolar macrophages, but not other lung immune cells, acquire aging hallmarks and decline in number, as observed in chronological aging. This established that deficiency of a nuclear envelope component can represent a cell-intrinsic model of accelerated aging in specific immune cell types. In preliminary results, further explorations revealed that subsets of skin immune cells are also decreased in a mouse model of nuclear envelope deficiency. Interestingly, the same skin immune cells are decreased in the aged skin of humans and mice. Nicolas Manel’s project will test the hypothesis that loss of nuclear envelope integrity is a mechanism of aging in these skin immune cells. It aims to define the mechanisms leading to skin immune cell depletion, the impact on the immune cell homeostasis in the skin, and the pathophysiological consequences of such depletion in skin immunity against age-related pathologies.
The results of the project have the potential to reveal new fundamental pathways in the aging of skin immunity and its impact on the health of aged individuals.
Functional analysis of the genomic abnormalities of non UV-induced skin squamous cell carcinomas
Grantee: Dany Nassar, MD, PhD, Associate Professor, Department of Dermatology, Université Paris
Amount: DKK 952,095
Grant category: Research Grants in open competition
Year: 2017
Geography: France
Squamous cell carcinoma (SCC) of the skin is the second most frequent skin cancer. Generally, SCC occurs on sun-exposed areas of fair skinned in elderly individuals.
However, skin carcinogenesis is also observed in non-UV induced settings, particularly in chronic wounds and scars like chronic leg ulcers, inherited blistering diseases and deep burn scars. These wound-associated SCCs are highly invasive and prone to metastasis, making them a life threatening complication.
The mechanisms of chronic wound carcinogenesis are unknown. The absence of UV exposure and different clinical behaviour suggest different mechanisms of carcinogenesis, including different initiating driver genomic abnormalities.
The team behind this study aims to uncover genomic alterations through Whole Exome Sequencing on a cohort of 35 wound/scar-associated SCCs with matching germline DNA. They will compare achieved data to data on UV-induced SCCs and to murine models of skin SCCs.
Furthermore, they will perform micro-dissection of successive stages of carcinogenesis in a cohort of specimen and subject these to targeted genotyping. This will allow for determination of the successive genetic alterations that drive the multistep carcinogenesis in the absence of carcinogenic UV exposure.
The team expects to find a distinct and hopefully new mutational signature in skin carcinogenesis, to identify new oncogenes and tumour suppressor genes and to model the multistep genomic evolution of wound/scarring associated skin SCC.
Basis for the project lies in a multicentre collaboration gathering six University Hospitals in two countries, including Paris-based Hôpital Cochin and Hôpital Tenon as well as American University of Beirut Medical Centre in Lebanon.