A New Method to Develop PET Ligands for Protein Aggregates in Neurodegenerative Disorders Using Soluble Brain-Derived Aggregates

使用可溶性脑源性聚集体开发神经退行性疾病中蛋白质聚集体 PET 配体的新方法

• 批准号: EP/T01427X/1
• 负责人: David Klenerman
• 金额: $ 99.77万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FT01427X%2F1
• 关键词: New; Method; Develop; PET; Ligands

A common feature of all dementias e.g. Alzheimer's, Parkinson's and Huntington's diseases are the presence of specific proteins in the brain, which due to having abnormal structures, accumulate into increasingly large assemblies and fibrils. These structures, which are present in many regions of the brain, are considered to be toxic and damage brain cells, leading to the symptoms of dementia. Using the clinical brain imaging technique of Positron Emission Tomography (PET) combined with injecting into patients chemical probes, which selectively bind to these assembles, we can now visualize the presence and distribution of some of these toxic proteins. However, with the present range of these chemical probes we can only image the late stages of these assemblies when most of the brain damage has occurred and so too late for effective drugs therapies. Therefore, our aim is to develop a general method to find the next generation chemical probes that can image the earlier stages and structures of these abnormal proteins when they are considered most toxic and hence cause the most damage to brains cells. This would then create a powerful means for earlier more accurate diagnosis of dementia and a means of evaluating the new types of drugs that are been developed that target these assemblies. To do this we will extract small amounts of soluble toxic aggregates from samples of brain tissue from patients who unfortunately died with a neurodegenerative disease and directly image the binding of labelled probes to these aggregates, using a very sensitive fluorescence method that we have developed that can detect single aggregates. This method will directly test binding to the aggregates in humans and needs only very small amounts of reagents. Once we have probes that bind to the soluble aggregates we can see if other unlabelled potential probes can remove them and hence more rapidly screen for better probes that will work in humans and can be used to detect the aggregates formed at early stages of disease.

所有痴呆例如阿尔茨海默病、帕金森病和亨廷顿病的共同特征是脑中存在特定蛋白质，其由于具有异常结构而积累成越来越大的组装体和原纤维。这些结构存在于大脑的许多区域，被认为是有毒的，会损害脑细胞，导致痴呆症的症状。使用正电子发射断层扫描（PET）的临床脑成像技术，结合向患者体内注射化学探针，选择性地结合这些组合物，我们现在可以可视化这些有毒蛋白质的存在和分布。然而，以目前这些化学探针的范围，我们只能在大部分脑损伤发生时对这些组装的晚期进行成像，因此对于有效的药物治疗来说为时已晚。因此，我们的目标是开发一种通用的方法来寻找下一代化学探针，可以成像这些异常蛋白质的早期阶段和结构，当它们被认为是最有毒的，因此对脑细胞造成最大的损害。这将为早期更准确地诊断痴呆症创造一种强大的手段，并为评估针对这些组件开发的新型药物提供一种手段。为此，我们将从不幸死于神经退行性疾病的患者的脑组织样本中提取少量可溶性毒性聚集体，并使用我们开发的可以检测单个聚集体的非常灵敏的荧光方法直接成像标记探针与这些聚集体的结合。该方法将直接测试与人类聚集体的结合，并且仅需要非常少量的试剂。一旦我们有了与可溶性聚集体结合的探针，我们就可以看到其他未标记的潜在探针是否可以去除它们，从而更快地筛选出更好的探针，这些探针将在人类中起作用，并可用于检测在疾病早期形成的聚集体。

项目成果

Constructing a cost-efficient, high-throughput and high-quality single-molecule localization microscope for super-resolution imaging.

构建具有成本效益、高通量和高质量的单分子定位显微镜，用于超分辨率成像。

• DOI: 10.17863/cam.89187
• 发表时间: 2022
• 作者: Danial J

Single molecule imaging of protein aggregation in Dementia: Methods, insights and prospects.

• DOI: 10.1016/j.nbd.2021.105327
• 发表时间: 2021-06
• 期刊: Neurobiology of disease
• 影响因子: 6.1
• 作者: Danial JSH;Klenerman D
• 通讯作者: Klenerman D

Constructing a cost-efficient, high-throughput and high-quality single-molecule localization microscope for super-resolution imaging

• DOI: 10.1038/s41596-022-00730-6
• 发表时间: 2022-08-24
• 期刊: NATURE PROTOCOLS
• 影响因子: 14.8
• 作者: Danial, John S. H.;Lam, Jeff Y. L.;Klenerman, David
• 通讯作者: Klenerman, David