A Semi-Automated Antibody-Discovery Platform to Target Challenging Biomolecules
针对具有挑战性的生物分子的半自动化抗体发现平台
基本信息
- 批准号:MR/Y003616/1
- 负责人:
- 金额:$ 75.72万
- 依托单位:
- 依托单位国家:英国
- 项目类别:Fellowship
- 财政年份:2024
- 资助国家:英国
- 起止时间:2024 至 无数据
- 项目状态:未结题
- 来源:
- 关键词:
项目摘要
A major bottleneck in biomedical research is the scarcity of tools to study disease mechanisms directly in their 'true' biological environments, such as in living being, in an accurate manner. A remarkable example of the implications of this technology gap is given by our current understanding of dementia. Dementia is an umbrella term referring to a set of incurable diseases, including Alzheimer's, Parkinson's, and frontotemporal dementia. Altogether, these pathologies currently affect more than 50 million people worldwide. Despite this prevalence of dementia, we still lack effective diagnostic and therapeutic molecules for it because of the sparse information on the pathological mechanisms. A major mechanism of dementia is the formation of protein clusters in the nervous system, which are associated with cellular death. Over the last two decades, researchers have focused on understanding protein clustering under highly controlled experimental conditions using proteins in isolation (in vitro approaches). These accurate studies have contributed to the understanding of the physical laws that regulate protein clustering; nevertheless, they have also provided an overly simplistic picture of the clustering mechanism. They did not account for the many events in the nervous system, as proven by the fact that protein clusters isolated from patients are heavily chemically modified and tightly associated with other biomolecules, including nucleic acids.Because of their specific binding to targets, antibodies represent a fast-growing class of protein drugs and find a wide application as probes in biomedical research. Antibodies allow scientists to bridge highly precise in vitro measurements with the use of highly complex biological samples. Nevertheless, despite their potential, the use of antibodies is still hindered by challenges associated with their production. Antibody discovery can be a lengthy and costly procedure. Furthermore, several biomolecules, such as chemically modified proteins, protein clusters, and nucleic acids, are challenging to target with standard antibody-discovery approaches, despite these biomolecules being highly prevalent in diseases, e.g., dementia. The goal of this project is to deliver an innovative, generally applicable antibody-discovery technology able to target protein clusters which are chemically modified or in complex with other biomolecules, such as nucleic acids. To achieve our goal, we will work on two systems, the protein FUS and the transactive response DNA-binding protein 43 (TDP-43), involved in amyotrophic lateral sclerosis, frontotemporal dementia and Alzheimer's disease. Both proteins have been reported to undergo several types of chemical modifications and to bind to different RNA molecules. We will develop antibodies using our integrative discovery platform with the addition of a semi-automated screening component to target clusters of the proteins of interest carrying chemical modifications and/or in complex with RNAs associated with the disease. Thus, we will use the antibodies to monitor the distribution of the protein-RNA aggregates in human tissue. Our results will provide novel information on these diseases and lead to a generally applicable time- and cost-effective antibody-discovery technology to produce antibodies against biomolecules beyond proteins.
生物医学研究中的一个主要瓶颈是缺乏直接在“真实”生物环境中(如生物)以准确的方式研究疾病机制的工具。我们目前对痴呆症的理解是这种技术差距影响的一个显著例子。痴呆症是一个总括性术语,指的是一系列无法治愈的疾病,包括阿尔茨海默氏症,帕金森氏症和额颞叶痴呆症。目前,这些疾病总共影响到全世界5 000多万人。尽管痴呆症的患病率很高,但我们仍然缺乏有效的诊断和治疗分子,因为关于其病理机制的信息很少。痴呆症的一个主要机制是神经系统中蛋白质簇的形成,这与细胞死亡有关。在过去的二十年里,研究人员一直专注于使用分离的蛋白质(体外方法)在高度受控的实验条件下理解蛋白质聚类。这些精确的研究有助于理解调节蛋白质聚集的物理定律;然而,它们也提供了一个过于简单的聚集机制。从病人身上分离出来的蛋白质簇经过了大量的化学修饰,并与包括核酸在内的其他生物分子紧密结合,这一事实就证明了这一点。由于抗体与靶点的特异性结合,抗体代表了一类快速增长的蛋白质药物,并在生物医学研究中作为探针得到了广泛的应用。抗体使科学家能够使用高度复杂的生物样品进行高度精确的体外测量。然而,尽管它们具有潜力,但抗体的使用仍然受到与其生产相关的挑战的阻碍。抗体发现可能是一个漫长而昂贵的过程。此外,几种生物分子,如化学修饰的蛋白质、蛋白质簇和核酸,具有用标准抗体发现方法靶向的挑战性,尽管这些生物分子在疾病中高度流行,例如,痴呆该项目的目标是提供一种创新的、普遍适用的抗体发现技术,能够靶向经过化学修饰或与其他生物分子(如核酸)复合的蛋白质簇。为了实现我们的目标,我们将研究两个系统,蛋白质FUS和交互反应DNA结合蛋白43(TDP-43),涉及肌萎缩侧索硬化症,额颞叶痴呆症和阿尔茨海默病。据报道,这两种蛋白质都经历了几种类型的化学修饰,并与不同的RNA分子结合。我们将使用我们的综合发现平台开发抗体,并添加半自动筛选组件,以靶向携带化学修饰和/或与疾病相关的RNA复合的感兴趣蛋白质簇。因此,我们将使用抗体来监测蛋白质-RNA聚集体在人体组织中的分布。我们的研究结果将提供关于这些疾病的新信息,并导致普遍适用的时间和成本效益的抗体发现技术,以产生针对蛋白质以外的生物分子的抗体。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Francesco Aprile其他文献
Heterogeneity of the Departments of Mental Health in the Veneto Region ten years after the National Plan 1994-96 for Mental Health. Which implication for clinical practice? Findings from the PICOS Project
1994-96 年国家心理健康计划十年后,威尼托大区心理健康部门的异质性。
- DOI:
- 发表时间:
2007 - 期刊:
- 影响因子:0
- 作者:
A. Lasalvia;B. Gentile;M. Ruggeri;Alessandro Marcolin;Flavio Nosè;Lodovico Cappellari;D. Lamonaca;E. Toniolo;C. Busana;Antonio Campedelli;G. Cuccato;Andrea Danieli;F. D. De Nardi;V. De Nardo;Ernesto Destro;G. Favaretto;S. Frazzingaro;M. Giacopuzzi;Paolo Pristinger;Giuseppe Pullia;Sandro Rodighiero;P. Tito;Francesco Aprile;S. Nicolaou;G. Coppola;N. Garzotto;Umberto Gottardi;E. Lazzarin;Giuseppe Migliorini;L. Pavan;Fabrizio Ramaciotti;Paolo Roveroni;S. Russo;P. Urbani;M. Tansella - 通讯作者:
M. Tansella
Francesco Aprile的其他文献
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{{ truncateString('Francesco Aprile', 18)}}的其他基金
Probing Post-Translational Modification in Neurodegenerative Protein Aggregation with a Novel Antibody-Based Technology
利用基于抗体的新型技术探索神经退行性蛋白质聚集的翻译后修饰
- 批准号:
MR/S033947/1 - 财政年份:2020
- 资助金额:
$ 75.72万 - 项目类别:
Fellowship
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