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

Hutchinson-Gilford Progeria综合征(HGPS)是一种罕见的遗传性疾病，由LMNA基因的新基因突变引起，导致错误拼接和产生截短的Lamin A蛋白，称为孕激素。儿童表现出加速衰老的典型症状，并在十几岁时死于加速的动脉粥样硬化和心血管疾病。潜在的致病机制仍不清楚，临床试验仅显示出有限的成功。基于该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、组织和组织水平上的病理HGPS标志特征存在因果联系。这些研究包括ncRNAs在HGPS连锁错误剪接事件中的作用，损伤诱导的ncRNAs在DNA损伤反应(DDR)激活和诱导细胞衰老中的作用，以及细胞内和分泌的microRNAs(MiRs)在心血管组织促纤维化信号中的作用。最先进的心血管组织单细胞水平的测序技术将被用于识别内皮细胞特异性和系统性HGPS小鼠模型中的ncRNAs，以及患者的成纤维细胞和诱导的多能干细胞以及相关椎板病患者的各种组织中的ncRNAs。识别的ncRNAs将进行功能测试，以确定它们是否参与细胞HGPS疾病模型中的DDR、错误剪接和促纤维化信号传递。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。在HGPS的背景下，ncRNAs是迄今未被探索的一个方面。我们希望我们的联盟将确定与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、反义寡核苷酸)的新的、更有效的治疗方法铺平道路。这个跨国和跨学科的项目涉及来自瑞典、意大利、奥地利和德国的首席研究人员，包括hgps小鼠模型和细胞表型分子生物学分析方面的专家，参与椎板病患者诊断和治疗的临床研究人员，以及世界上最大的早衰症患者倡导组织(prf https://www.progeriaresearch.org).)。

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).