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（如多发性和肌萎缩性侧索硬化症、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，在全球人口老龄化趋势下变得越来越具有挑战性。尽管有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改善疗法。到目前为止，治疗重点仅限于少数下游疾病标志（例如淀粉样斑块、tau蛋白、α突触核蛋白），而神经变性的复杂病理生理学涉及多个生物参与者。神经炎症最近已经成为针对神经变性认知下降的新的、有吸引力的靶标[1]，并且促炎性microRNA的小家族已经被认为是神经炎症的致病诱导物，这可能会引发功能和精神障碍[2 - 5]。我们的目标是通过研究选择性敲除这种病理相关的microRNA是否可以将信号通路从“患病”转换为“正常”来验证这一假设。鉴于目前的敲除问题，我们将应用我们的创新（神经抗miRs）来选择性地运输，识别和不可逆地破坏促炎microRNAs。通过监测神经变性细胞模型、人脑组织和动物认知模型在暴露于这些药剂后的生物反应，我们将研究这些促炎microRNA是否可以被认为是疾病发展的可能治疗靶点-深入了解神经炎症在神经退行性疾病的诱导和进展中的作用对于未来开发新的治疗方法至关重要。针对促炎诱导物的治疗策略。由于miRNA上调出现在神经退行性过程的相对早期阶段，因此敲除干预可以在患病细胞中建立神经炎症的神经病理学后果之前阻止疾病进展，并阻止旁分泌扩散到健康组织中。这项研究的结果将揭示，（单独或组合）可以用作有效靶向神经炎症的治疗机会。如果成功，这项研究将为这种新的治疗平台提供概念验证，并加速神经抗miR创新的转化发展，以改善疾病的治疗发现和临床前开发，从而促进神经变性治疗的行业投资。