In vivo stress reporters as early biomarkers of the cellular changes associated with progeria.
In vivo stress reporters as early biomarkers of the cellular changes associated with progeria.
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DOI：
10.1111/jcmm.17574
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发表时间：
2022-11
影响因子：
5.3
通讯作者：
中科院分区：
文献类型：
--
作者：
与年龄相关的疾病在全球疾病总负担中所占比例很高。尽管最近在了解其分子基础方面取得了进展，但仍缺乏合适的早期生物标志物来测试选定的化合物并加速其转化为临床试验。我们研究了体内应激报告系统作为退行性疾病进展的替代早期生物标志物的效用。我们假设在人类退行性疾病模型中观察到的细胞应激先于明显的细胞损伤，同时将识别潜在的细胞保护途径。为了检验这一假设，我们通过将 LmnaG609G 小鼠杂交到我们的氧化应激/炎症 (Hmox1) 和 DNA 损伤 (p21) 应激报告模型中，生成了新型加速衰老（早衰）报告小鼠。报告基因表达的组织学分析表明，在与早衰症直接相关的组织中，包括平滑肌细胞、脉管系统和胃肠道，报告基因的激活具有时间依赖性和组织特异性。重要的是，报告基因的表达在任何可察觉的有害表型之前就被检测到。因此，报告基因表达可用作早衰症发病机制的早期标志物并测试治疗干预措施。这项工作还展示了使用压力报告方法来研究和寻找其他退行性疾病新疗法的潜力。
Age‐related diseases account for a high proportion of the total global burden of disease. Despite recent advances in understanding their molecular basis, there is a lack of suitable early biomarkers to test selected compounds and accelerate their translation to clinical trials. We have investigated the utility of in vivo stress reporter systems as surrogate early biomarkers of the degenerative disease progression. We hypothesized that cellular stress observed in models of human degenerative disease preceded overt cellular damage and at the same time will identify potential cytoprotective pathways. To test this hypothesis, we generated novel accelerated ageing (progeria) reporter mice by crossing the LmnaG609G mice into our oxidative stress/inflammation (Hmox1) and DNA damage (p21) stress reporter models. Histological analysis of reporter expression demonstrated a time‐dependent and tissue‐specific activation of the reporters in tissues directly associated with Progeria, including smooth muscle cells, the vasculature and gastrointestinal tract. Importantly, reporter expression was detected prior to any perceptible deleterious phenotype. Reporter expression can therefore be used as an early marker of progeria pathogenesis and to test therapeutic interventions. This work also demonstrates the potential to use stress reporter approaches to study and find new treatments for other degenerative diseases.
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影响因子：
64.5
作者：
López-Otín C;Blasco MA;Partridge L;Serrano M;Kroemer G
通讯作者：
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作者：
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通讯作者：
Lopez-Otin, Carlos
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82.9
作者：
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通讯作者：
Lopez-Otin, Carlos