Molecular mechanisms underlying defects in adipogenesis in lipodystrophic laminopathies

• Applicant: Professorin Dr. Karima Djabali
• Subject Area: Dermatology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 539360217

Hutchinson-Gilford Progeria Syndrome (HGPS), Mandibuloacral Dysplasia (MADB), and Familial Partial Lipodystrophy (FPLD2) are rare genetic disorders characterized by the accumulation of farnesylated progerin or prelamin A, leading to nuclear envelope (NE) rigidity and compromised cellular functions. These aberrant proteins may interfere with adipogenesis, the differentiation process of mesenchymal stem cells into adipocytes. This study aims to elucidate the underlying molecular mechanisms disrupting adipogenesis in the presence of these lamin A variants. We employ skin-derived precursor cells (SKPs) harvested from patients with HGPS, MADB, FPLD2, and normal individuals as experimental models. Our research is organized around two specific aims: (1) to assess the impact of lamin A variants on cytoskeletal dynamics and nucleoskeletal interactions during adipogenesis, focusing on RhoA/ROCK and RAC1/PAK1 signaling pathways, and (2) to perform comprehensive transcriptomic analyses to identify gene expression changes and disrupted signaling pathways. We will employ mRNA next-generation sequencing, qPCR, western blotting, and pathway analyses to achieve these objectives. Findings from this study could reveal new targets for therapeutic interventions and improve our understanding of lipodystrophy disorders.

• DFG Programme: Research Grants