The rarest of the rare – exploring non-coding RNA in the disease pathogenesis of Hutchinson-Gilford progeria syndrome

罕见中的罕见 探索非编码RNA在Hutchinson-Gilford早衰综合征疾病发病机制中的作用

• 批准号: 441083670
• 负责人: Professorin Dr. Karima Djabali
• 金额: --
• 依托单位: Department für Biochemie und Zellbiologie
• 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/441083670?language=en
• 关键词: rarest; rare; exploring; non; coding

Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare genetic disorder, caused by a de novo point mutation in the LMNA gene, leading to mis-splicing and production of a truncated lamin A protein, named progerin. Children show typical symptoms of accelerated aging and die in their teens due to accelerated atherosclerosis and cardiovascular disease. The underlying patho-mechanisms remain unclear, and clinical trials have shown only limited success. Based on exciting recent work of consortium members we hypothesize that non-coding RNAs (ncRNAs) are causally linked to pathological HGPS hallmark features at the cell, tissue and organismal level. These include the role of ncRNAs in HGPS-linked mis-splicing events, the contribution of damage-induced ncRNAs to DNA damage response (DDR) activation and induction of cellular senescence, and the role of intracellular and secreted micro RNAs (miRs) in pro-fibrotic signaling in cardiovascular tissue. State-of-the-art sequencing technologies at the single-cell level in cardiovascular tissue will be employed to identify ncRNAs in endothelial cell-specific- and in systemic HGPS mouse models, as well as in fibroblasts and induced pluripotent stem cells of patients and in various tissues of related laminopathic patients. Identified ncRNAs will be functionally tested for their involvement in DDR, mis-splicing, and pro fibrotic signalling in cellular HGPS disease models. Finally, we will use oligonucleotide-based drugs against the most promising ncRNAs in HGPS mouse models to study their causal involvement in disease pathology and test their potential as novel therapeutic reagents. ncRNAs are a hitherto underexplored aspect in the context of HGPS. We expect that our consortium will identify ncRNA-linked HGPS disease pathways, which can pave the way to new, more efficient therapeutic approaches based on ncRNA-neutralizing reagents (antisense oligos, antagomiRs). The transnational and interdisciplinary project involves principal investigators from Sweden, Italy, Austria and Germany, including experts in HGPS mouse models and in molecular biological analyses of cellular phenotypes, clinical researcher involved in diagnosis and treatment of laminopathic patients and the world-wide largest progeria patient advocacy organization (PRF https://www.progeriaresearch.org).

哈钦森-吉尔福德早衰综合征（HGPS）是一种罕见的遗传疾病，由LMNA基因的新生点突变引起，导致错误剪接和产生截断的层状蛋白a蛋白，称为早衰蛋白。儿童表现出加速衰老的典型症状，由于动脉粥样硬化和心血管疾病的加速，他们在十几岁时死亡。潜在的病理机制尚不清楚，临床试验仅显示有限的成功。基于联盟成员最近令人兴奋的工作，我们假设非编码rna （ncRNAs）与细胞、组织和组织水平的病理HGPS标志特征有因果关系。这些研究包括ncRNAs在hgps相关的错误剪接事件中的作用，损伤诱导的ncRNAs对DNA损伤反应（DDR）激活和诱导细胞衰老的贡献，以及细胞内和分泌的微rna （miRs）在心血管组织中促纤维化信号传导中的作用。最先进的心血管组织单细胞水平测序技术将用于鉴定内皮细胞特异性和全身性HGPS小鼠模型中的ncrna，以及患者的成纤维细胞和诱导多能干细胞以及相关层层病患者的各种组织中的ncrna。鉴定出的ncrna将在细胞HGPS疾病模型中参与DDR、错误剪接和促纤维化信号的功能测试。最后，我们将在HGPS小鼠模型中使用基于寡核苷酸的药物来对抗最有希望的ncrna，以研究它们在疾病病理中的因果关系，并测试它们作为新型治疗试剂的潜力。迄今为止，在HGPS的背景下，ncrna是一个未被充分探索的方面。我们希望我们的联盟能够确定与ncrna相关的HGPS疾病途径，这可以为基于ncrna中和试剂（反义寡核苷酸，拮抗剂）的新的更有效的治疗方法铺平道路。这项跨国和跨学科的项目涉及来自瑞典、意大利、奥地利和德国的主要研究人员，包括HGPS小鼠模型和细胞表型分子生物学分析的专家，参与层状病变患者诊断和治疗的临床研究人员以及世界上最大的早衰患者倡导组织（PRF https://www.progeriaresearch.org）。