Project Details
Projekt
Disease stratification, treatment monitoring and establishment of model systems
Subject Area
Orthopaedics, Traumatology, Reconstructive Surgery
Term
since 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 517063424
In the context of the clinical research unit ProBone (“Precision Medicine for Early-Onset Low Bone Mineral Density Disorders”), this project (P1) has the role to identify patients with early-onset low bone mineral density (BMD) and to provide, after exclusion of known secondary causes, samples to other ProBone partners. P1 will also document more than 100 clinical parameters for each patient (at least 100 patients per year expected), which will be systematically evaluated, assisted by the ProBone central project 2 (CP2). Another key focus of P1 is to monitor, with the same diagnostic panel as applied at first visit, the influence of existing treatment options, if initiated. P1 will also be responsible for the generation, provision and baseline analysis of genetically modified mouse models for specific early-onset low BMD disorders. Moreover, in close collaboration with the ProBone central project 1 (CP1), human induced pluripotent stem cells (hiPSCs) generated from patient-derived primary urinary cells will be functionally studied by various assays, including omics approaches, in collaboration with the ProBone projects P4 and P6. Besides following an unbiased approach, which essentially involves the whole cohort of patients diagnosed with early-onset low BMD, P1 has already formulated specific subprojects focusing on presumably relevant and poorly understood molecular pathways controlling skeletal integrity. First, based on our previous studies demonstrating a remarkable osteoanabolic influence of WNT1, we will analyze whether osteogenic differentiation of hiPSCs is enhanced by WNT1, and if specific genetic variants impair this response. Second, given a unique high turnover low BMD pathology observed in a patient with a likely disease-causing variant of a poorly understood skeletal disease gene, i.e. TMEM53, we will perform cellular assays, together with the ProBone projects P3 and P6, to understand the molecular functions of TMEM53. Third, we will expand our previous analysis regarding the low BMD phenotype of mice carrying a pathogenic variant of Sms, encoding spermine synthase, since we had previously identified pathogenic SMS variants in two unrelated patients with early-onset low BMD. The overall aim of P1, which requires the close collaboration with all ProBone partners, is to apply precision medicine in order to identify a definite disease cause, either genetic (P3) or non-genetic (P6 and P7), at least for the vast majority of individuals affected by early-onset low BMD. Moreover, we expect to obtain novel and clinically relevant molecular insights into specific genetic pathways profoundly affecting bone mass and/or matrix mineralization. The ultimate goal of P1, which would also extend into a second funding period, is a personalized treatment of respective patients, to prevent further BMD loss and, most importantly, skeletal fractures.
DFG Programme
Clinical Research Units
