Molecular mechanisms underlying defects in adipogenesis in lipodystrophic laminopathies

脂肪营养不良核纤层蛋白病脂肪生成缺陷的分子机制

• 批准号: 539360217
• 负责人: Professorin Dr. Karima Djabali
• 金额: --
• 依托单位: Munich School of BioEngineering
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/539360217?language=en
• 关键词: Molecular; mechanisms; underlying; defects; adipogenesis

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.

Hutchinson-Gilford早衰综合征（HGPS）、下颌骨肢端发育不良（MADB）和家族性部分脂肪营养不良（FPLD 2）是罕见的遗传性疾病，其特征在于法尼基化早老蛋白或层蛋白前体A的积累，导致核膜（NE）僵硬和细胞功能受损。这些异常蛋白质可能干扰脂肪生成，即间充质干细胞向脂肪细胞的分化过程。本研究旨在阐明这些核纤层蛋白A变异体存在下破坏脂肪形成的潜在分子机制。我们采用从HGPS、MADB、FPLD 2患者和正常个体中收获的皮肤来源的前体细胞（SKPs）作为实验模型。我们的研究围绕两个具体目标组织：（1）评估核纤层蛋白A变体对脂肪形成过程中细胞骨架动力学和核骨架相互作用的影响，重点是RhoA/ROCK和RAC 1/PAK 1信号通路，以及（2）进行全面的转录组学分析，以确定基因表达变化和中断的信号通路。我们将采用mRNA下一代测序、qPCR、蛋白质印迹和途径分析来实现这些目标。这项研究的结果可以揭示治疗干预的新靶点，并提高我们对脂肪代谢障碍的理解。