Disease pathogenicity in Hutchinson-Gilford progeria syndrome mice: insights from lung-associated alterations.

IF 6 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Jingjing Wang, Yuelin Guan, Yue Wang, Junyi Tan, Zhongkai Cao, Yuhan Ding, Langping Gao, Haidong Fu, Xiangjun Chen, Jianyu Lin, Ning Shen, Xudong Fu, Fangqin Wang, Jianhua Mao, Lidan Hu
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引用次数: 0

Abstract

Background: Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by accelerated aging, impaired growth, disrupted lipid metabolism, and reduced lifespan.

Methods: Prior research has primarily focused on cardiovascular manifestations, our research sheds light on multiple organs that underwent significant age-related changes validated by tissue cross-sections H&E, Masson's trichrome, and β-galactosidase staining.

Results: Among these pathologies tissues, the lung was severely affected and substantiated by clinical data of pulmonary anomalies from our HGPS patients. Biochemical and histological analyses of lung tissue from the HGPS mouse model revealed elevated Progerin expression, abnormal NAD metabolism, cellular senescence markers (higher level of p16 and p27, lower level of ki67), and various age-related morphology changes, including fibrosis, inflammation, and thickening of alveolar walls. Transcriptomic analyses of lung tissue indicated that down-regulated genes (Thy1, Tnc, Cspg4, Ccr1) were associated with extracellular space, immune response, calcium signaling pathway, osteoclast differentiation, and lipid binding pathway.

Conclusions: This study unveiled the previously overlooked organs involved in HGPS pathogenesis and suggested a specific emphasis on the lung. Our findings suggest that pulmonary abnormalities may contribute to disease progression, warranting further investigation into their role in HGPS monitoring and management.

哈钦森-吉尔福德早衰综合征小鼠的疾病致病性:来自肺部相关改变的见解
背景:Hutchinson-Gilford早衰综合征(HGPS)是一种罕见的遗传性疾病,其特征是衰老加速、生长受损、脂质代谢紊乱和寿命缩短。方法:先前的研究主要集中在心血管表现上,我们的研究通过组织横断面H&E,马松三色和β-半乳糖苷酶染色证实了多个器官发生了显著的年龄相关变化。结果:在这些病理组织中,肺部受到的影响最为严重,我们的HGPS患者肺部异常的临床资料证实了这一点。HGPS小鼠模型肺组织的生化和组织学分析显示,Progerin表达升高,NAD代谢异常,细胞衰老标志物(p16和p27水平升高,ki67水平降低),以及各种与年龄相关的形态学变化,包括纤维化、炎症和肺泡壁增厚。肺组织转录组学分析表明,下调基因(Thy1、Tnc、Cspg4、Ccr1)与细胞外空间、免疫应答、钙信号通路、破骨细胞分化和脂质结合通路有关。结论:本研究揭示了先前被忽视的HGPS发病机制中涉及的器官,并建议特别强调肺。我们的研究结果表明,肺部异常可能导致疾病进展,值得进一步研究其在HGPS监测和管理中的作用。
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来源期刊
Molecular Medicine
Molecular Medicine 医学-生化与分子生物学
CiteScore
8.60
自引率
0.00%
发文量
137
审稿时长
1 months
期刊介绍: Molecular Medicine is an open access journal that focuses on publishing recent findings related to disease pathogenesis at the molecular or physiological level. These insights can potentially contribute to the development of specific tools for disease diagnosis, treatment, or prevention. The journal considers manuscripts that present material pertinent to the genetic, molecular, or cellular underpinnings of critical physiological or disease processes. Submissions to Molecular Medicine are expected to elucidate the broader implications of the research findings for human disease and medicine in a manner that is accessible to a wide audience.
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