儿童早衰症中的NRF2通路研究

Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare, invariably fatal premature aging disorder. The disease is caused by constitutive production of progerin, a mutant form of the nuclear architectural protein lamin A, leading through unknown mechanisms to extensive morphological, epigenetic and genomic damage and to mesenchymal stem cell (MSC) attrition in vivo. Using a high-throughput siRNA screen primary data have identified the NRF2 antioxidant pathway is a key regulator in premature aging. To study whether NRF2 pathway is a driver mechanism in HGPS, we plan to study whether Progerin could directly bind to NRF2 and thereby causes its subnuclear mislocalization or degeneration, resulting in impaired NRF2 transcriptional activity and consequently increased chronic oxidative stress. Suppressed NRF2 activity by knock down experiment will increase oxidative stress, which may recapitulate HGPS aging defects. On other hand, re-activation of NRF2 activity in HGPS patient cells reverses progerin-associated nuclear aging defects and restores in vivo viability of MSCs in animal model will be studied. Our study will identify repression of the NRF2-mediated antioxidative response as a key contributor to the premature aging phenotype.

儿童早衰症（HGPS）是一种由核纤层蛋白Lamin A突变导致的极其罕见的先天性疾病。HGPS影响多种不同的细胞衰老途径，而且这些途径密切交织相互影响。这为剖析HGPS中最为关键的直接致病途径制造了障碍。为寻找HGPS发病机理的直接因素，申请人拟利用基于HGPS细胞的高通量筛选技术，对影响细胞衰老表型的各个蛋白因子进行筛选。利用这一体系，前期结果已经发现NRF2介导的抗氧化途径在HGPS致病机理中至关重要。根据这一重要线索，后续将进一步深入研究NRF2信号通路在HGPS和自然衰老中的作用机理。通过NRF2基因敲减和过表达正反两反面的研究深入阐述NRF2如何行驶衰老过程中的核心关键作用。本研究将为开发基于NRF2抗氧化途径的衰老干预方法提供理论基础。

儿童早衰症（HGPS）是一种罕见的、致命性的早衰症。该疾病是由于编码核膜蛋白Lamin A的基因发生突变，导致早老素progerin积累，通过未知的机制导致体内多种形态学改变，表观遗传学改变和基因组损伤以及间充质干细胞（MSC）的损耗。在这里，我们通过高通量siRNA筛选，确定NRF2是HGPS病理表现的驱动因素，progerin通过与NRF2相互作用，引起NRF2的细胞核定位错误，NRF2转录活性受损，细胞的慢性氧化应激反应增加。抑制NRF2活性或增加氧化应激足以重现HGPS衰老缺陷，而在HGPS患者细胞中重新激活NRF2活性可以逆转与progerin相关的核衰老缺陷，并恢复动物模型中MSCs的体内活力。这些发现表明，NRF2介导的抗氧化反应的抑制是导致过HGPS表型的关键因素。