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(如多发性和肌萎缩侧索硬化症、阿尔茨海默病和帕金森病)具有巨大的心理、临床和社会影响，在全球人口老龄化的趋势下变得越来越具有挑战性。尽管进行了巨大的技术和财政投资，但还没有发现一种针对这些目前无法治愈的疾病的疾病修正疗法。到目前为止，治疗重点仅限于少数下游疾病特征(如淀粉样斑块、tau蛋白、α-突触核蛋白)，而神经退行性变的复杂病理生理学涉及多个生物因子。神经炎症最近已成为对抗神经退行性认知衰退的新的、有吸引力的靶点[1]，一小类促炎microRNAs被认为是神经炎症的致病诱因，可引发功能和智力损伤[2-5]。我们在这里的目的是通过研究选择性地敲除这种与病理相关的microRNAs是否可以将信号通路从“病态”切换到“正常”来检验这一假说。鉴于目前的击倒问题，我们将应用我们的创新(神经抗miRs)来选择性地运输、识别和不可逆转地破坏促炎microRNA。通过监测神经退行性变细胞模型、人脑组织和动物认知模型对这些药物的生物反应，我们将调查这些促炎微RNA是否可以被视为开发针对神经退行性疾病的疾病修改治疗的可能治疗靶点。深入了解神经炎症在神经退行性疾病的诱导和发展中的作用对于未来开发针对促炎诱导物的新的治疗策略至关重要。由于miRNA上调出现在神经退变过程的相对早期阶段，基因敲除干预可能会在神经炎症的神经病理后果在病变细胞中确定之前阻止疾病的进展，并阻止旁分泌扩散到健康组织。这项研究的结果将揭示已识别的促炎microRNA(单独或联合使用)是否可以用作有效靶向神经炎症的治疗机会。如果成功，这项研究将为这一新的治疗平台提供概念验证，并加快将神经抗miR创新转化为疾病修改治疗发现和临床前开发，转向对神经变性治疗的行业投资。