CoEN Developing preclinical and clinical biomarkers of NRF2 pathway activation for therapeutic application in neurodegenerative diseases.

CoEN 开发 NRF2 通路激活的临床前和临床生物标志物，用于神经退行性疾病的治疗应用。

• 批准号: MR/S004920/1
• 负责人: Pamela Shaw
• 金额: $ 52.12万
• 依托单位: University of Sheffield
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS004920%2F1
• 关键词: CoEN; Developing; preclinical; clinical; biomarkers

Neurodegenerative diseases such as Alzheimer's (AD) and motor neuron disease (ALS/MND) cause cell death of different populations of nerve cells. These conditions are very distressing for sufferers and their families. There is a severe lack of treatments available to slow disease progression and clinical trials have had high failure rates partly because there is no way to demonstrate that a drug is reaching the nervous system in the right amounts to protect the nerve cells from injury. Although the underlying causes that trigger these diseases are complex (multiple genes and environmental factors), there is substantial overlap in the cell pathways that lead to neurodegeneration.This project is focused on a master cellular pathway (sometimes called the programmed cell-life pathway) controlled by a molecule NRF2 that promotes cell survival in the face of stresses such as oxidative stress, inflammation, and failure of the energy-generating and protein quality-control pathways within neurons which are known to contribute to neurodegeneration. Our aim is to develop MRI imaging and body fluid markers to show NRF2-activating drugs working in the body. These results will be applied later in clinical trials to test the effectiveness of NRF2 activators for patients with MND and AD.

阿尔茨海默病(AD)和运动神经元病(ALS/MND)等神经退行性疾病会导致不同群体神经细胞的细胞死亡。这些情况对患者及其家人来说非常令人痛苦。目前严重缺乏减缓疾病进展的治疗方法，临床试验的失败率很高，部分原因是无法证明一种药物正在以正确的数量到达神经系统，以保护神经细胞免受伤害。虽然引发这些疾病的潜在原因很复杂(多基因和环境因素)，但导致神经退化的细胞途径有很大的重叠。该项目专注于由NRF2分子控制的主要细胞途径(有时称为编程细胞生命途径)，该分子促进细胞在面临诸如氧化应激、炎症和神经元内能量产生和蛋白质质量控制途径的失败等压力时存活，这些都是已知导致神经退化的因素。我们的目标是开发核磁共振成像和体液标志物，以显示激活NRF2的药物在体内发挥作用。这些结果将在稍后的临床试验中应用，以测试NRF2激活剂对MND和AD患者的有效性。

项目成果

Additional file 10 of SRSF1-dependent inhibition of C9ORF72-repeat RNA nuclear export: genome-wide mechanisms for neuroprotection in amyotrophic lateral sclerosis

SRSF1依赖性抑制C9ORF72重复RNA核输出的附加文件10：肌萎缩侧索硬化症神经保护的全基因组机制

• DOI: 10.6084/m9.figshare.15145929
• 发表时间: 2021
• 作者: Castelli L

SRSF1-dependent inhibition of C9ORF72-repeat RNA nuclear export: genome-wide mechanisms for neuroprotection in amyotrophic lateral sclerosis.

• DOI: 10.1186/s13024-021-00475-y
• 发表时间: 2021-08-10
• 期刊: Molecular neurodegeneration
• 影响因子: 15.1
• 作者: Castelli LM;Cutillo L;Souza CDS;Sanchez-Martinez A;Granata I;Lin YH;Myszczynska MA;Heath PR;Livesey MR;Ning K;Azzouz M;Shaw PJ;Guarracino MR;Whitworth AJ;Ferraiuolo L;Milo M;Hautbergue GM
• 通讯作者: Hautbergue GM

Directly converted astrocytes retain the ageing features of the donor fibroblasts and elucidate the astrocytic contribution to human CNS health and disease.

• DOI: 10.1111/acel.13281
• 发表时间: 2021-01
• 期刊: Aging cell
• 影响因子: 7.8
• 作者: Gatto N;Dos Santos Souza C;Shaw AC;Bell SM;Myszczynska MA;Powers S;Meyer K;Castelli LM;Karyka E;Mortiboys H;Azzouz M;Hautbergue GM;Márkus NM;Shaw PJ;Ferraiuolo L
• 通讯作者: Ferraiuolo L

Additional file 16 of SRSF1-dependent inhibition of C9ORF72-repeat RNA nuclear export: genome-wide mechanisms for neuroprotection in amyotrophic lateral sclerosis

SRSF1依赖性抑制C9ORF72重复RNA核输出的附加文件16：肌萎缩侧索硬化症神经保护的全基因组机制

• DOI: 10.6084/m9.figshare.15145947
• 发表时间: 2021
• 作者: Castelli L

Creatine kinase and prognosis in amyotrophic lateral sclerosis: a literature review and multi-centre cohort analysis.

• DOI: 10.1007/s00415-022-11195-8
• 发表时间: 2022-10
• 期刊: JOURNAL OF NEUROLOGY
• 影响因子: 6
• 作者: Gao, Jiali;Dharmadasa, Thanuja;Malaspina, Andrea;Shaw, Pamela J.;Talbot, Kevin;Turner, Martin R.;Thompson, Alexander G.
• 通讯作者: Thompson, Alexander G.