Project Details
Projekt
Spatial transcriptome mapping to identify druggable targets in the early-intermediate progression of bone marrow fibrosis
Applicants
Dr. Sikander Hayat; Professor Dr. Rafael Kramann
Subject Area
Hematology, Oncology
Term
since 2019
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 417911533
Despite the enormous progress in the elucidation of potential therapeutic targets and increased understanding of the disease pathophysiology in general, the cellular targets of myelofibrosis have remained obscure for many years and are far less understood than in solid organ fibrosis. Single cell RNA-sequencing allows to gain precise understanding of cellular heterogeneity but lacks spatial information which is critical for understanding tissue homeostasis and disease. We will perform high-resolution spatial transcriptomics combined with single cell RNA-sequencing in time-course experiments of JAK2V617F and CALR induced myelofibrosis in mice and human bone marrow biopsies from patients with myelofibrosis and controls. Data will be integrated and analyzed to identify targets and cell-type specific disease-associated gene-regulatory networks to understand which mechanisms occur across species which will be critical for translation and preclinical drug development. Targets will be validated using advanced three dimensional culture techniques and induced pluripotent stem cell derived hematopoietic cells as well as mesenchymal stem cells combined with CRISPR/Cas9 inhibition or activation of expression and available tool compounds.
DFG Programme
Clinical Research Units
