Grants Awarded

Date of Award
December 2018

Amount of Award
$50,000

Layperson Summary

The aim of this project is to understand cellular and molecular mechanisms that contribute to LCH pathogenesis. LCH is a heterogeneous disease. The clinical course can be relatively harmless with lesions resolving spontaneously, but it can also be life threatening and cause substantial morbidity and mortality. The unifying factor in LCH is the accumulation of the CD1a+ CD207+ LCH cell in different tissues, most commonly bone and skin, but currently it is unclear how and if these cells reflect the clinical behavior. For instance, the staining of a bone biopsy from a patient with single system disease does not differ from one of a patient with multisystem disease. Yet, by looking at the LCH cells within the lesions more closely, we might uncover factors that can help us to understand this disease better. Here we propose to analyze the methylome – unique DNA methylation patterns – of the LCH cell, and compare it to different cell types isolated from the blood and tissue of healthy donors. DNA methylation can be compared to a ‘cellular memory’ and its analysis provides an excellent tool to study relationships between cell types. By using this approach, we will gain insight into the precursor cells of LCH. To investigate how lesions develop, we will employ single cell RNA-Sequencing, which allows us to investigate gene expression in the individual LCH cells. We can then use computational methods to infer developmental pathways within LCH lesions. Furthermore, the analysis of the RNA data will enable us to identify specific subtypes of LCH cells. We will then correlate the presence of these subtypes with clinical information in order to find out whether they are associated with a certain clinical behavior. Together, these data will help us to better understand this disease and provide the basis to develop new strategies to predict clinical behavior and treat the individual patient.