Grants Awarded

Principal Investigator:
Egle Kvedaraite
Karolinska lnstitutet and Karolinska University Hospital,
Stockholm, Sweden

Date of Award:
December 2024

Amount of Award:
$51,000 (Founder’s Grant and Toughill Prize)

Layperson Summary:

ECD is a rare disease that can affect many different organs, including the brain. A certain type of mutation called BRAFV600E as well as other mutations have been found in ECD tumor cells. The disease may be life-threatening, and new treatment targeting the mutation has significantly improved mortality in ECD patients, although neurodegenerative disease remains a challenge. In addition, once the treatment is stopped, the disease usually comes back. So how can we eliminate the mutant cell pool and specifically target neurodegeneration? What is the cell of tumor origin in ECD and what pathways promote tissue destruction, neurodegeneration, tumor survival? In what way the responses from the neighboring cells in the brain differ compared to other organs? These are the questions that we will tackle in the proposed research. We will use state-of-art techniques, and perform our investigations not on all cells together, but one cell at the time – using so called single-cell spatial techniques, that have been proven to be extremely helpful for understanding normal and mutated cells, and their different flavors. That is important, because those differences may be patient-specific, and to eliminate all tumor cells in a long run we need to first find out exactly what they are, and how they differ from each other. Relevance: This research will provide the first molecular definition of ECD at single cell spatial resolution. The focus is neurodegenerative histiocytic disease and ECD, but we will also perform comparative analyses with other types of histiocytosis in the brain (mixed type, LCH, RDD). This would generate the first detailed molecular and spatial atlas from the tissue site of neurodegeneration in histiocytic disorders that has potential to fuel novel research initiatives in the histiocytosis community. Potential benefits for histiocytosis patients: Patients with ECD and related histiocytosis usually relapse after targeted treatment is stopped. In addition, our understanding of mechanisms of neurodegeneration in histiocytosis is very limited, making it hard to treat. Our research aims to provide a data-driven translational platform for improved diagnostics and treatment through precision medicine for ECD patients and other histiocytosis patients suffering from the neurodegenerative disease.