Selective knockdown of proinflammatory microRNAs to tackle neurodegeneration and cognitive decline: myth or reality?

选择性敲除促炎性 microRNA 来解决神经退行性疾病和认知能力下降：神话还是现实？

• 批准号: 2628091
• 金额: --
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2628091
• 关键词: Selective; knockdown; proinflammatory; microRNAs; tackle

Neurodegenerative diseases (e.g. multiple and amyotrophic lateral sclerosis, Alzheimer's and Parkinson's diseases) have tremendous psychological, clinical and social impact, which becomes increasingly challenging in the global trend of population aging. Despite enormous technological and financial investments, not a single disease-modifying therapy has been discovered against these currently incurable diseases. Until now, the therapeutic focus was limited to only a few downstream disease hallmarks (e.g. amyloid plaques, tau protein, alpha synuclein), whereas complex pathophysiology of neurodegeneration involves multiple biological players.Neuroinflammation has recently emerged as a new, appealing target against neurodegenerative cognitive decline [1], and a small family of proinflammatory microRNAs has been suggested as pathogenic inducers of neuroinflammation, which can trigger functional and mental impairments [2-5]. We aim here to test this hypothesis by investigating whether selective knockdown of such pathology-associated microRNAs can switch signalling pathways from 'diseased' to 'normal'. Given current knockdown issues, we will apply our innovation (neuro-anti-miRs) to selectively transport, recognise and irreversibly destroy proinflammatory microRNAs. By monitoring biological responses in neurodegeneration cell models, human brain tissues and animal models of cognition upon exposure to these agents, we will investigate whether these proinflammatory microRNAs can be considered as possible therapeutic targets for development of disease-modifying treatments against neurodegeneration.Insight into the role of neuroinflammation in the induction and progression of neurodegenerative diseases is crucial for future development of new therapeutic strategies against proinflammatory inducers. As miRNA up-regulation appears at relative early stages of the neurodegenerative process, knockdown intervention may halt disease progression before neuropathology consequences of neuroinflammation are established in diseased cells, and to stop paracrine spread into healthy tissues.The outcomes of this research will reveal whether the identified pro-inflammatory microRNAs (alone or in combination) can be used as a therapeutic opportunity for effective targeting of neuroinflammation. If successful, this research will provide proof-of-concept of this new therapeutic platform and accelerate translational development of neuro-anti-miR innovation into disease-modifying therapeutic discovery and pre-clinical development, towards industry investment in neurodegeneration treatment.

神经退行性疾病（例如多种和肌萎缩性的侧面硬化症，阿尔茨海默氏症和帕金森氏病）具有巨大的心理，临床和社会影响，这在人口衰老的全球趋势中变得越来越具有挑战性。尽管有巨大的技术和金融投资，但还没有发现针对这些目前无法治愈的疾病的单一疾病改良疗法。 Until now, the therapeutic focus was limited to only a few downstream disease hallmarks (e.g. amyloid plaques, tau protein, alpha synuclein), whereas complex pathophysiology of neurodegeneration involves multiple biological players.Neuroinflammation has recently emerged as a new, appealing target against neurodegenerative cognitive decline [1], and a small family of proinflammatory microRNAs已被认为是神经炎症的致病诱导剂，可以触发功能和精神障碍[2-5]。我们的目的是通过研究这种病理相关的microRNA是否可以将信号通路从“患病”切换到“正常”来检验这一假设。鉴于当前的敲低问题，我们将应用创新（神经 - 抗激素）来有选择地运输，识别和不可逆转地破坏促炎的microRNA。通过监测神经退行性细胞模型中的生物学反应，接触这些药物后的人脑组织和动物认知模型，我们将调查这些促炎的microRNA是否可以被视为疾病 - 修饰治疗神经变性的疾病修饰的可能性治疗靶标，对神经变性的发展。针对促炎诱导剂的治疗策略。由于miRNA上调出现在神经退行性过程的相对早期阶段，因此在疾病细胞中建立了神经炎症的神经病理学后果之前，敲低干预可能会停止疾病进展，以阻止旁分泌扩散到健康组织中。神经炎症。如果成功的话，这项研究将为这个新的治疗平台提供概念验证，并加快神经抗抗激素创新的转化发展，以改善疾病改良的治疗发现和临床前开发，以实现神经变性治疗的行业投资。