Project Details
Projekt
Exploring the cross-talk between bone and the immune system in early-onset low BMD disorders
Applicant
Professorin Dr. Eva Tolosa
Subject Area
Orthopaedics, Traumatology, Reconstructive Surgery
Term
since 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 517063424
The cross-talk between bone and immune cells is long known. The bone provides the microenvironment for the development of immune cell precursors, and immune cells and their secreted products contribute to bone homeostasis. Loss of immune homeostasis, as it happens with acute immune responses or inflammation, can lead to bone destruction. Moreover, many of the known skeletal disease genes are expressed ubiquitously or in a cell-specific manner in immune cells, but the function of the translated proteins and the effects of the disease gene variants are unknown. Despite advancements in genetic analysis, for more than one third of patients with early-onset low BMD a pathogenic variant in genes associated to bone cannot be found. Therefore, we hypothesize that immune dysregulation may contribute to early-onset low BMD. Also, defects in skeletal genes that are expressed in immune cells, or the lifelong treatment required in these patients, may affect immune function. In project P7, we will work in close cooperation with P1 and P2 to obtain longitudinal blood samples of patients with early-onset low BMD for an in-depth immune profiling. Our first objective is to explore immune dysregulation as underlying cause of early-onset low BMD disorders in the absence of a monogenic bone-specific defect. Using targeted serum proteomics and flow cytometry analysis we will determine whether different pathways of innate or adaptive immunity are dysregulated in this subgroup of patients. Here we will work closely with P3 to recognize genes relevant for immune function among the candidates identified in these patients. Second, we will assess the impact of disease causative gene variants and of the treatment on the immune cell function in patients with early-onset low BMD disorders. Finally, and given the expertise of my lab on purinergic enzymes and T cell biology, we aim to decipher the yet unknown function of the purinergic enzymes TNSALP (cooperation with P5), expressed in neutrophils, ENPP1 (cooperation with P1), expressed in a specific subset of dendritic cells, and of IFITM5 (cooperation with P4), which is upregulated on T cells in immunity. Altogether, we expect to find new disease-causing genes for early-onset low BMD and to assess the quality of the immune response in the respective patients, also depending on bone-specific treatment.
DFG Programme
Clinical Research Units
