Transcriptomic analysis and validation of neuroprotective candidates for the development of innovative diagnostic and therapeutic targets in neurology

神经保护候选药物的转录组分析和验证，用于开发神经病学创新诊断和治疗靶点

• 批准号: 289331510
• 负责人: Dr. Alexander Schulz, Ph.D.
• 金额: --
• 依托单位: Department of Genetics
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/289331510?language=en
• 关键词: Transcriptomic; analysis; validation; neuroprotective; candidates

This research proposal aims to identify neuroprotective candidates by transcriptome analysis of injured neurons, for the development of innovative diagnostic and therapeutic targets in neurology. To date, clinical neurology suffers from the blatant situation that the majority of both acute and chronic CNS disorders cannot be treated in a curative or causal fashion. Importantly, most neurological diseases share one striking similarity: the death of neuronal cells is what produces malfunctions and symptoms in affected individuals. This is why one solving strategy would be the prevention, or at least the delay, of neuronal death while a harmful stimulus risks the survival of neurons. Armed with a better understanding of how neurons mechanistically react to survival-threatening injuries, the field of neuroprotection and neurology could be positively transformed. With appropriate knowledge of signaling events that are beneficial and detrimental for the cell fate, appropriate and selective therapeutic interference might be able to prolong cell survival and to prevent cell death. Data from various preconditioning experiments and selective neuronal vulnerability already provide biological evidence that this is attainable. However, little is known about the exact molecular mechanism that takes place in neurons after injury or damage. By performing a combination of separate transcriptome analyses by means of RNA sequencing; where three independent models of neurodegeneration are used to determine a common transcriptomic signature shared by newly injured neurons, this research proposal aims to identify key components and potentially druggable targets of neuron damage response. To validate the sequencing results derived from murine primary cortical neurons, the animal model C. elegans will be applied; taking advantage of the easy and established tools to establish genetically modified animals and the ability to perform neuron injury experiments at the single-cell level in vivo. The striking advantage of this research project is the fact that we have performed transcriptome analysis from mammalian tissue and will transfer the results a step back in evolutionary terms. This means that all validated neuroprotective candidates automatically have a mouse homologue and can be applied in a mammalian test system at a later time point. Long-term, the goal of this research proposal is to decipher fundamental mechanisms of neuronal damage that could be useful in the diagnosis and therapy of a variety of neurological disorders. By finding genes or proteins with a highly specific expression in stressed neuronal cells (neurons at risk), it would not just be possible to create new biological tools and animal models for further research, but also to develop techniques that could improve the diagnosis and the staging of brain disorders.

该研究计划旨在通过对受损神经元的转录组分析来识别神经保护候选物，以开发神经病学的创新诊断和治疗靶点。迄今为止，临床神经病学遭受的公然的情况下，大多数急性和慢性中枢神经系统疾病不能治疗的治愈或因果的方式。重要的是，大多数神经系统疾病都有一个惊人的相似之处：神经元细胞的死亡是受影响个体产生功能障碍和症状的原因。这就是为什么一个解决策略是防止或至少延迟神经元死亡，而有害的刺激会危及神经元的存活。更好地理解神经元如何机械地对危及生存的损伤做出反应，神经保护和神经学领域可能会发生积极的转变。通过适当了解对细胞命运有益和有害的信号传导事件，适当和选择性的治疗干预可能能够延长细胞存活并防止细胞死亡。来自各种预处理实验和选择性神经元脆弱性的数据已经提供了生物学证据，表明这是可以实现的。然而，很少有人知道确切的分子机制，发生在神经元损伤或损害后。通过RNA测序进行单独的转录组分析的组合;其中三个独立的神经变性模型用于确定新损伤的神经元共享的共同转录组特征，该研究提案旨在确定神经元损伤反应的关键组分和潜在的药物靶点。为了验证来自小鼠原代皮层神经元的测序结果，动物模型C。将使用elegans;利用容易和已建立的工具来建立转基因动物和在体内单细胞水平上进行神经元损伤实验的能力。这项研究项目的显著优势是，我们已经从哺乳动物组织中进行了转录组分析，并将结果转移到进化方面。这意味着所有经验证的神经保护候选物自动具有小鼠同源物，并且可以在稍后的时间点应用于哺乳动物测试系统。从长远来看，这项研究计划的目标是破译神经元损伤的基本机制，这可能有助于诊断和治疗各种神经系统疾病。通过发现在应激神经元细胞（处于危险中的神经元）中具有高度特异性表达的基因或蛋白质，不仅可以为进一步研究创造新的生物工具和动物模型，而且还可以开发可以改善大脑疾病诊断和分期的技术。

项目成果

The stress-responsive gene GDPGP1/mcp-1 regulates neuronal glycogen metabolism and survival

• DOI: 10.1083/jcb.201807127
• 发表时间: 2020-01
• 期刊: The Journal of Cell Biology
• 作者: A. Schulz;Y. Sekine;Motunrayo J Oyeyemi;Alexander Abrams;Manasa Basavaraju;S. M. Han;Marco Groth;H. Morrison;S. Strittmatter;Marc Hammarlund