Biomarker Discovery: Ubiquitin Pathway Protein Microarrays

生物标志物发现：泛素通路蛋白质微阵列

• 批准号: 7939939
• 负责人: James Strickler
• 金额: $ 39.34万
• 依托单位: LIFESENSORS, INC.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-20 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7939939
• 关键词: Antibodies; Antibody Formation; Basic Science; Biochemical; Bioinformatics; Biological Assay; Biological Markers; Blood; Cardiovascular Diseases; Cell Survival; Cell physiology; Cells; Clinical; Clinical Research; Collaborations; Complex; Deubiquitinating Enzyme; Development; Development Plans; Diabetes Mellitus; Diagnosis; Diagnostic; Disease; Early Diagnosis; Enzyme-Linked Immunosorbent Assay; Enzymes; Escherichia coli; Fred Hutchinson Cancer Research Center; Goals; Grant; Health; Homeostasis; Human; Human Genome; Human Ubiquitin; Inflammatory; Insecta; Institutes; Laboratories; Lead; Ligase; Malignant Neoplasms; Mediating; Molecular Profiling; Monitor; Names; Nerve Degeneration; Neurodegenerative Disorders; Pathology; Pathway interactions; Patient Monitoring; Phase; Play; Polyubiquitin; Population; Printing; Progress Reports; Protein Microchips; Proteins; Regulation; Research; Research Personnel; Role; Sampling; Screening procedure; Serum; Source; Speed; Staging; Surface; Technology; Testing; Therapeutic; Therapeutic Effect; Tissue Sample; Tissues; Ubiquitin; Ubiquitin Like Proteins; United States Centers for Medicare and Medicaid Services; United States Food and Drug Administration; United States National Institutes of Health; Validation; Yin-Yang; base; disease diagnosis; drug development; drug discovery; enzyme pathway; meetings; member; multicatalytic endopeptidase complex; new therapeutic target; novel therapeutics; outcome forecast; polyclonal antibody; product development; prognostic; protein expression; public health relevance; repository; research and development; success; therapeutic target; tool

DESCRIPTION (provided by applicant): Bioinformatics and biochemical analysis suggests that the human genome encodes ~ 100 proteins known as deubiquitinating enzymes (DUBs). DUBs constitute an important class of enzymes that deconjugate ubiquitin and ubiquitin-like proteins (UBL) from their target proteins. Protein uniquitination serves many functions in the cell, including proteasome-mediated degradation of poly-ubiquitin tagged proteins. DUBs are thus key regulators that play a very important role in the fate of cellular proteins. In Phase I it was proposed to study a limited number of DUBs to test the feasibility of a catalytically active array as well as a DUB array for serum biomarkers. This study has been completed successfully and, for Phase II, LifeSensors plans to develop an array covering most of the deUBLases and selected Ub-ligases (UBL-enzymes) for profiling serum samples; specifically, two types of array are proposed: (1) a complete UBL-enzyme antibody array to monitor signature(s) of UBL-enzymes associated with disease and normal states; and (2) an array in which all of the UBL enzymes are utilized to monitor human sera for auto-antibodies that may serve as biomarkers in health and disease. UBL-enzyme microarrays developed in this study will represent important advances for research, biomarker discovery, diagnostics/prognostics, and therapeutics. The ubiquitin pathway is the most conserved pathway of eukaryotic origin. Aberrations in such highly conserved pathways are likely to lead to pathologies. The expression of various DUBs has been associated with diseases such as cancer, diabetes, and neurodegenerative disease (PD, AD), to name a few. Over- or under-expression of proteins in disease states tend to elicit elevated or diminished auto-antibody production against those proteins. Thus, auto-antibody profiling can help to identify the type and stage of a disease. The ubiquitin pathway and DUBs in particular are emerging as sources of novel therapeutic targets, and the development of UBL-enzyme arrays that identify signatures in disease tissue will doubtless facilitate target validation as well as serve as biomarkers. Given the Phase I success, a comprehensive plan for the development of UBL-enzyme microarrays from the human genome has been proposed. A key aspect of this plan is a collaboration with the Fred Hutchinson Cancer Research Center wherein the new UBL-enzyme biomarker arrays will be characterized by screening from among the institute's many human serum repositories. PUBLIC HEALTH RELEVANCE: The ubiquitin- and ubiquitin-related pathways play a central role in cellular homeostasis and regulation. These pathways involve a Yin/Yang of conjugation and deconjugation of the small ubiquitin-like proteins to target proteins. Dysregulation of these pathways has been implicated in cancer, inflammatory and cardiovascular diseases, and neurodegeneration. LifeSensors proposes to develop an assay technology for the majority of the members of these pathways, over 100 distinct proteins. This assay has the potential to identify new biomarkers for the early diagnosis of these diseases.

描述（由申请人提供）：生物信息学和生化分析表明，人类基因组编码约 100 种被称为去泛素化酶 (DUB) 的蛋白质。 DUB 是一类重要的酶，可将泛素和泛素样蛋白 (UBL) 从其靶蛋白上解偶联。蛋白质单素化在细胞中具有多种功能，包括蛋白酶体介导的多聚泛素标记蛋白质的降解。因此，DUB 是关键的调节因子，在细胞蛋白质的命运中发挥着非常重要的作用。在第一阶段，建议研究有限数量的 DUB，以测试催化活性阵列以及血清生物标志物 DUB 阵列的可行性。这项研究已成功完成，在第二阶段，LifeSensors 计划开发一种阵列，涵盖大多数 deUBLases 和选定的 Ub 连接酶（UBL 酶），用于分析血清样本；具体而言，提出了两种类型的阵列：（1）完整的UBL酶抗体阵列，用于监测与疾病和正常状态相关的UBL酶的特征； (2) 一个阵列，其中所有 UBL 酶都用于监测人类血清中的自身抗体，这些抗体可以作为健康和疾病的生物标志物。本研究中开发的 UBL 酶微阵列将代表研究、生物标志物发现、诊断/预后和治疗方面的重要进展。泛素途径是真核起源的最保守的途径。这种高度保守的通路中的畸变可能会导致病理学。各种 DUB 的表达与癌症、糖尿病和神经退行性疾病（PD、AD）等疾病有关。疾病状态下蛋白质的过度表达或表达不足往往会引起针对这些蛋白质的自身抗体产生升高或降低。因此，自身抗体分析可以帮助识别疾病的类型和阶段。泛素通路，特别是 DUB，正在成为新型治疗靶点的来源，而识别疾病组织中特征的 UBL 酶阵列的开发无疑将促进靶点验证并作为生物标志物。鉴于第一阶段的成功，已经提出了从人类基因组开发 UBL 酶微阵列的综合计划。该计划的一个关键方面是与 Fred Hutchinson 癌症研究中心的合作，其中新的 UBL 酶生物标记物阵列将通过从该研究所的许多人类血清存储库中进行筛选来表征。公共健康相关性：泛素和泛素相关途径在细胞稳态和调节中发挥着核心作用。这些途径涉及小泛素样蛋白与靶蛋白的结合和解结合的阴/阳。这些途径的失调与癌症、炎症和心血管疾病以及神经退行性疾病有关。 LifeSensors 提议为这些途径的大多数成员（100 多种不同的蛋白质）开发一种检测技术。该测定有可能识别用于这些疾病早期诊断的新生物标志物。