GluR-5

▎药明康德内容团队编辑   当今世界正面临人口结构老龄化的严峻挑战，伴随老龄化的加剧, 诸如肝纤维化、肺纤维化、癌症、骨关节炎以及神经退行性疾病等与细胞衰老相关的疾病，已成为不容忽视的重要健康问题。清除衰老细胞有望缓解甚至治疗这些衰老相关疾病，这一观点已在领域内形成共识。然而，如何安全、有效且精准地清除衰老细胞仍然是目前亟待攻克的难题。 2024年12月2日，浙江大学医学院附属第二医院/转化医学研究院王本教授团队在Nature Aging期刊在线发表论文，提出了一种全新的、安全且可持续的清除衰老细胞的方法。这种方法通过构建特异性靶向衰老细胞并激活免疫反应的嵌合多肽分子药物，促进免疫细胞识别并杀伤衰老细胞，从而缓解衰老相关的病理特征。小鼠实验显示，研究团队设计的嵌合多肽分子药物可有效抵抗自然衰老。 研究作者介绍，机体免疫系统中的固有免疫反应是清除衰老细胞的天然机制，对维持内环境稳态起着至关重要的作用，因此，寻找激活内源性免疫系统的新方法是抗衰领域的一个重要方向和突破口。 这项研究的策略是使用嵌合多肽分子为免疫细胞和衰老细胞“牵线搭桥”。以往的研究显示，谷氨酸与免疫细胞的静息与激活显著相关，或可作为启动内源性免疫反应的调节剂；尿激酶型纤溶酶原激活剂受体（uPAR）则是衰老细胞广泛和特异性表达的细胞表面蛋白。因此研究人员基于uPAR特异性配体尿激酶型纤溶酶原激活剂（uPA）靶向结合区域序列设计合成一段长度约24个氨基酸的靶向多肽uPA24，搭载16个重复序列谷氨酸（16E），构建了嵌合多肽E16-uPA24，可有效地标记衰老细胞，通过谷氨酸识别免疫细胞并促进其介导的免疫反应。 ▲嵌合多肽分子对衰老微环境中免疫细胞的影响（图片来源：研究团队提供） 为阐明E16-uPA24对纤维化衰老免疫微环境的影响，研究人员收集了小鼠的正常肝组织、纤维化肝组织、经多肽治疗后的纤维化肝组织，使用质谱流式对免疫细胞进行分群分析。结果显示，与肝纤维化组相比，治疗组中的促炎细胞（中性粒细胞、嗜酸性粒细胞）数量比例呈下降趋势；而淋巴细胞，特别是自然杀伤（NK）细胞的比例则明显增加。这表明，E16-uPA24可通过增强淋巴细胞毒性杀伤作用来调节器官衰老的微环境，其中NK细胞可能发挥了关键作用。 进一步的体内外实验验证显示，该嵌合多肽既能够靶向uPAR结合在衰老细胞膜上，又能作用于NK细胞膜上的谷氨酸受体5（mGluR5），从而增强NK细胞识别和清除衰老细胞，改善包括慢性肝纤维化、急性肺纤维化等衰老相关疾病，并可以有效抵抗自然衰老。 ▲抗衰老治疗模式图（图片来源：研究团队提供） 研究团队向学术经纬指出，鉴于目前临床上对衰老细胞的精准判断还较为困难，通过衰老标记物、人工智能等多种技术组合识别和表征衰老细胞，并使用更加安全高效的免疫调节剂平衡人体的免疫微环境，实现对组织内衰老细胞的准确识别和清除，可为临床精准治疗衰老相关疾病甚至延缓自然衰老进程提供新的方向。 Nature Aging同期对该研究刊发了题为“Restoring aging-related tissue homeostasis via reactivated innate immunotherapy”的Research Briefing（研究简报）， 报道了该项研究成果，并附有西班牙坎塔布里亚生物医学与生物技术研究所Juan Carlos Acosta Cobacho教授和Nature Aging编辑团队的积极评价。 浙江大学医学院转化医学研究院/附属第二医院王本教授为该论文的通讯作者，转化医学院明心亮博士（现浙二医院检验科工作）、博士生杨泽、黄裕乔为共同第一作者。本研究得到浙江大学吕志民教授，杭州师范大学王志国研究员等学者的指导和帮助。 参考资料： [1] Ming, X., Yang, Z., Huang, Y. et al. A chimeric peptide promotes immune surveillance of senescent cells in injury, fibrosis, tumorigenesis and aging. Nat Aging (2024). https://doi.org/10.1038/s43587-024-00750-9 本文来自药明康德内容微信团队，欢迎转发到朋友圈，谢绝转载到其他平台。如有开设白名单需求，请在“学术经纬”公众号主页回复“转载”获取转载须知。其他合作需求，请联系wuxi_media@wuxiapptec.com。 免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。 更多推荐 点个“在看”再走吧~

编辑丨王多鱼 排版丨水成文 “最是人间留不住，朱颜辞镜花辞树”。岁月带给我们容颜变化的同时，我们身体内在的组织细胞也在缓慢发生衰老, 衰老过程中衰老细胞的累积是器官和机体衰老的重要驱动力。当今世界正面临人口结构老龄化的严峻挑战，伴随老龄化的加剧, 诸如肝纤维化、肺纤维化、癌症、骨关节炎以及神经退行性疾病等与细胞衰老相关的疾病，已成为不容忽视的重要健康问题。 清除衰老细胞有望缓解甚至治疗这些衰老相关疾病，这一观点已在领域内形成共识。然而，如何安全、有效且精准地清除衰老细胞仍然是目前亟待攻克的难题。机体免疫系统中的固有免疫反应，是清除衰老细胞的天然机制，对维持内环境稳态起着至关重要的作用。因此，寻找激活内源性免疫系统的新方法，恢复免疫功能的平衡，从而缓解衰老相关疾病的进程，是抗衰领域的重要方向和突破口。 2024年12月2日，浙江大学医学院附属第二医院/转化医学研究院王本教授团队在 Nature Aging 期刊发表了题为：A chimeric peptide promotes immune surveillance of senescent cells in injury, fibrosis, tumorigenesis and aging 的研究论文。 该研究提出了一种全新的、安全且可持续的清除衰老细胞的方法。通过构建特异性靶向衰老细胞并激活免疫反应的嵌合多肽分子药物，为免疫细胞和衰老细胞“牵线搭桥”，促进免疫细胞识别并杀伤衰老细胞，从而有效清除衰老细胞，缓解衰老相关的病理特征，并可以有效抵抗自然衰老。 有研究报道，谷氨酸与免疫细胞的静息与激活显著相关，谷氨酸可能可以作为启动内源性免疫反应的调节剂。在人体衰老过程中，谷氨酸水平下降，免疫系统功能下降，谷氨酸补充可能有助于调节衰老个体的免疫细胞活性。另外已有研究确定尿激酶型纤溶酶原激活剂受体 (uPAR) 为衰老细胞中广泛和特异性表达的细胞表面蛋白。研究团队基于uPAR特异性配体尿激酶型纤溶酶原激活剂（uPA）靶向结合区域序列设计合成一段长度约24个氨基酸的靶向多肽uPA24并搭载16个重复序列谷氨酸(16E)构建了嵌合多肽E16-uPA24，可以有效地标记衰老细胞。 为阐明E16-uPA24对纤维化衰老免疫微环境的影响，研究团队收集了小鼠的正常肝组织，纤维化肝组织与经多肽治疗后的纤维化肝组织，并使用质谱流式对免疫细胞进行分群分析。结果显示，与肝纤维化组相比，治疗组中促炎性粒细胞（嗜酸性粒细胞）数量比例显著下降，中性粒细胞呈下降趋势；而淋巴细胞，特别是自然杀伤（NK）细胞的比例则明显增加。这表明，E16-uPA24可通过增强淋巴细胞毒性杀伤作用来调节器官衰老的微环境，其中NK细胞可能发挥了关键作用。 嵌合多肽E16-uPA24抗衰老治疗模式图 在进一步的体内外实验验证中，研究团队观察到该嵌合多肽既能够靶向uPAR结合在衰老细胞膜上，又能作用于NK细胞膜上的谷氨酸受体5（mGluR5），为NK细胞与衰老细胞“牵线搭桥”，从而增强NK细胞识别和清除衰老细胞，改善包括慢性肝纤维化、急性肺纤维化等衰老相关疾病，并可以有效抵抗自然衰老。 Nature Aging 期刊同期对该研究刊发了题为：Restoring aging-related tissue homeostasis via reactivated innate immunotherapy 的Research Briefing（研究简报）， 报道了该项研究成果，并附有西班牙坎塔布里亚生物医学与生物技术研究所Juan Carlos Acosta Cobacho教授和Nature Aging编辑团队的积极评价。 浙江大学医学院转化医学研究院/附属第二医院王本教授为该论文的通讯作者，浙江大学医学院转化医学院明心亮博士（现在浙二医院检验科工作），博士生杨泽、黄裕乔为论文共同第一作者。 论文链接： https://www.nature.com/articles/s43587-024-00750-9 设置星标，不错过精彩推文 开放转载 欢迎转发到朋友圈和微信群  微信加群  为促进前沿研究的传播和交流，我们组建了多个专业交流群，长按下方二维码，即可添加小编微信进群，由于申请人数较多，添加微信时请备注：学校/专业/姓名，如果是PI/教授，还请注明。 点在看，传递你的品味

Researchers have succeeded in restoring lost brain function in mouse models of stroke using small molecules that in the future could potentially be developed into a stroke recovery therapy. Researchers have succeeded in restoring lost brain function in mouse models of stroke using small molecules that in the future could potentially be developed into a stroke recovery therapy. "Communication between nerve cells in large parts of the brain changes after a stroke and we show that it can be partially restored with the treatment," says Tadeusz Wieloch, senior professor of neurobiology at Lund University in Sweden. "Concomitantly, the rodents regain lost somatosensory functions, something that around 60 per cent of all stroke patients experience today. The most remarkable result is that the treatment began several days after a stroke," Wieloch continues. In an ischemic stroke, lack of blood flow to the brain causes damage, which rapidly leads to nerve cell loss that affects large parts of the the vast network of nerve cells in the brain. This may lead to loss of function such as paralysis, sensorimotor impairment and vision and speech difficulties, but also to pain and depression. There are currently no approved drugs that improve or restore the functions after a stroke, apart from clot-dissolving treatment in the acute phase (within 4.5 hours of the stroke). Some spontaneous improvements occur, but many stroke patients suffer chronic loss of function. For example, about 60 per cent of stroke sufferers, experience lost somatosensori functions such as touch and position sense. An international study published recently in the journal Brain and led by a research team from Lund University in collaboration with University of Rome La Sapeinza and Washington University at St. Louis, shows promising results in mice and rats that were treated with a class of substances that inhibit the metabotropic glutamate receptor (mGluR5), a receptor that regulates communication in the brain's nerve cell network. "Rodents treated with the GluR5 inhibitor regained their somatosensori functions," says Tadeusz Wieloch, who led the study published in BRAIN. Two days after the stroke, i.e. when the damage had developed and function impairment was most prominent, the researchers started treating the rodents that exhibited the greatest impaired function. "A temporary treatment effect was seen after just 30 minutes, but treatment for several weeks is needed to achieve a permanent recovery effect. Some function improvement was observed even when the treatment started 10 days after a stroke," says Tadeusz Wieloch. Importantly, sensorimotor functions improved, even though the extent of the brain damage was not diminished. This, explains Tadeusz Wieloch, is due to the intricate network of nerve cells in the brain, known as the connectome, i.e. how various areas of the brain are connected and communicate with each to form the basis for various brain functions. "Impaired function after a stroke is due to cell loss, but also because of reduced activity in large parts of the connectome in the undamaged brain. The receptor mGluR5 is apparently an important factor in the reduced activity in the connectome, which is prevented by the inhibitor which therefore restores the lost brain function," says Tadeusz Wieloch. The results also showed that sensorimotor function was further improved if treatment with the mGluR5 inhibitor is combined with somatosensory training by housing several rodents in cages enriched with toys, chains, grids, and plastic tubes. The researchers hope that in the future their results could lead to a clinical treatment that could be initiated a few days after an ischemic stroke. "Combined with rehabilitation training, it could eventually be a new promising treatment. However, more studies are needed. The study was conducted on mice and rats, and of course needs to be repeated in humans. This should be possible since several mGluR5 inhibitors have been studied in humans for the treatment of neurological diseases other than stroke, and shown to be tolerated by humans," says Tadeusz Wieloch. The research is conducted with support from the Swedish Research Council, Alborada Trust, Hans-Gabriel and Alice Wachtmeister Foundation, and Multipark Strategic Research Area.