Developing ubiquitin chain- and target-specific deubiquitinase probes

开发泛素链和靶标特异性去泛素酶探针

• 批准号: 8772352
• 负责人: Zhihao Zhuang
• 金额: $ 19.5万
• 依托单位: UNIVERSITY OF DELAWARE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8772352
• 关键词: Address; Cell physiology; Cells; Chemicals; Cleaved cell; Collaborations; Complex; Cysteine; Deubiquitination; Development; Disease; Esters; Eukaryotic Cell; Generations; Human; Immunoprecipitation; Intervention; Investigation; Label; Length; Letters; Ligation; Link; Lysine; Malignant Neoplasms; Mass Spectrum Analysis; Methods; Nerve Degeneration; Neurodegenerative Disorders; Parkinson Disease; Pathogenesis; Physiological; Polyubiquitin; Proliferating Cell Nuclear Antigen; Proteins; Proteomics; Sampling; Small Interfering RNA; Specificity; Speed; Structure; Testing; Therapeutic; Therapeutic Intervention; UBD protein; Ubiquitin; Ubiquitination; Viral Cancer; Virus Diseases; abstracting; alpha synuclein; base; human disease; in vitro Assay; novel therapeutics; public health relevance; research study

DESCRIPTION (provided by applicant): Developing ubiquitin chain- and target protein-specific deubiquitinase probes Abstract Abnormal function of human deubiquitinases (DUBs) has been linked to the pathogenesis of a number of human diseases including neurodegenerative disorders, cancer and viral infection. Human DUBs are emerging as promising targets for pharmacological intervention. However, the lack of understanding of ubiquitin chain- and target protein-specificity of DUBs has hindered the progress in developing novel therapeutics. Although a myriad of cellular proteins have been found to be ubiquitinated, the DUBs or DUB complexes responsible for the deubiquitination of many of these proteins remain unknown. DUB probes that allow the identification of DUBs and the investigation of the chain and target protein specificity are highly desirable. This application focuses on the development a new class of DUB probes that contain an electrophilic group that can trap DUBs that contains a catalytic cysteine. The probes will be used to elucidate the polyubiquitin chain specificity of human DUBs and to identify DUBs specific for ubiquitinated protein α-synuclein that is implicated in Parkinson's disease. The DUB(s) responsible for α-synuclein deubiquitination will serve as a potential target for therapeutic intervention of Parkinson's disease (PD).

描述（由适用提供）：开发泛素链和靶蛋白特异性去泛素酶问题问题人类去泛素酶（DUB）的抽象异常功能与多种人类疾病的发病机理有关，包括神经退行性疾病，癌症和病毒感染。人类配音正作为药物干预的承诺目标而出现。然而，对配音的泛素链和靶蛋白特异性的不了解阻碍了发展新型治疗方面的进步。尽管已经发现无数的细胞蛋白是泛素化的，但负责许多这些蛋白质去泛素化的配音或DUB复合物仍然未知。高度希望可以识别配音以及链和目标蛋白质特异性的投资的DUB问题。该应用的重点是开发一类新的配音，该配音包含一个可以捕获含有催化半胱氨酸的配音的亲电群。这些问题将用于阐明人配音的多泛素链特异性，并识别帕金森氏病暗示的泛素化蛋白α-核蛋白特异性的配音。负责α-核蛋白去泛素化的配音将成为帕金森氏病治疗干预（PD）的潜在靶标。