Pathway-Guide: A novel tool for the analysis of signaling and metabolic pathways

通路指南：信号和代谢通路分析的新工具

• 批准号: 8201142
• 负责人: SORIN DRAGHICI
• 金额: $ 74.96万
• 依托单位: ADVAITA CORPORATION
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8201142
• 关键词: Aging; Architecture; Area; Back; Benchmarking; Biochemical Pathway; Biochemical Reaction; Biological; Biological Phenomena; Biological Sciences; Communities; Complex; Computer software; Custom; DNA Microarray Chip; Data; Databases; Dependency; Development; Disease; Drosophila genus; Drug Delivery Systems; Feedback; Gene Expression; Gene Proteins; Genes; Graph; Human; Intervention; Licensing; Life; Malignant Neoplasms; Measures; Metabolic Pathway; Methods; Modeling; Monitor; Mus; Obesity; Online Systems; Organism; Paper; Pathway Analysis; Pathway interactions; Pharmaceutical Preparations; Phase; Phenotype; Play; Positioning Attribute; Protein Microchips; Publishing; Reporting; Research; Research Personnel; Role; Signal Pathway; Signal Transduction; Signaling Pathway Gene; Small Business Technology Transfer Research; System; Systems Biology; Techniques; Testing; Therapeutic Intervention; Time; Training; Trust; Work; Yeasts; base; biological systems; commercialization; drug candidate; drug development; drug mechanism; metabolomics; neglect; novel; pathway tools; portability; prototype; research study; simulation; sound; tool; web site

DESCRIPTION (provided by applicant): Once heralded as the Holy Grail, the capability of obtaining a comprehensive list of genes, proteins or metabolites that are different between disease and normal is routine today. And yet, the holy grail of high-throughput has not delivered so far. Even though such high-throughput comparisons have become relatively easy to perform, understanding the phenomena that cause the disease is as challenging as ever, if not more so. Signaling and metabolic pathways are complex graphs describing genes signaling and biochemical reactions that take place in various subsystems of the organism. The current methods that aim to help us understand the underlying biological phenomena by using the measured differences to identify significantly impacted pathways are rather unsophisticated. Many if not all such methods of- ten treat the pathways as simple sets of genes, and either ignore or under-utilize the very essence of such pathways: the graphs that describe the complex ways in which genes interact with each other. We are proposing the development of a software product for the analysis of gene signaling and metabolic pathways in the context of high throughput data, such as DNA microarrays. The fundamentals of the approach have been tested through the implementation of tools available for free from the PI's academic web site. These tools have an existing user base of 11,266 registered users who already use and trust our software. This user-base constitutes a unique asset for Advaita. The product we envisage will have a number of unique capabilities including the ability to: i) take into consideration the interactions between specific genes; ii) calculate a unique "impact factor" that characterizes how impacted a given subsystem of the organism is in the given condition; iii) find the mechanisms of action for diseases and drugs; iv) pinpoint potential points of optimal therapeutic intervention; and v) detect qualitative changes in a living organism by monitoring a large number of parameters (gene expression levels, metabolites, etc.). This product has the potential to: i) shorten the drug development cycle by providing fewer but better drug candidates, ii) help with the understanding of disease and drug mechanisms, iii) detect qualitative changes in biological organisms. The scientific validity of this analysis approach has been verified on real data in a number of applications (several published, others described here as preliminary results). The technical feasibility was demonstrated in over 36,000 benchmark trials. The commercial validity of this product has been verified by implementing a proto- type including the first 2 of the capabilities above. This prototype was already sold to 3 customers in spite of the fact that it only implements a small subset of the final set of capabilities and in spite of the fact that these customers already had access to the software products offered by our competition. PUBLIC HEALTH RELEVANCE: The benefits of the proposed research are expected to impact a number of research areas spanning from cancer, to obesity, to aging as well as any other life science area in which high-throughput methods (e.g. DNA microarrays, protein microarrays, metabolomics, etc.) are used. The biological user community that can benefit from this research includes any life science researcher using such high-throughput methods in any biological domain and any organism, from yeast, to fruit fly, to mouse, to human.

描述（由申请人提供）：一旦将其视为圣杯，就可以在疾病和正常情况下获得不同基因，蛋白质或代谢物的全面列表的能力。然而，到目前为止，高通量的圣杯尚未交付。即使这样的高通量比较变得相对易于执行，但了解导致该疾病的现象与以往一样具有挑战性，即使不是更多。信号传导和代谢途径是描述基因信号传导和生化反应的复杂图，这些反应发生在生物体的各个子系统中。目前旨在通过使用测量差异来鉴定受到重大影响的途径来帮助我们了解潜在的生物学现象的当前方法是相当不合适的。许多这样的方法（十种）将途径视为简单的基因集，而忽略或忽略了这种途径的本质：描述基因相互作用的复杂方式的图。我们提出了在高吞吐量数据（例如DNA微阵列）中的基因信号传导和代谢途径分析的软件产品的开发。通过实施PI的学术网站免费实施工具，已测试了该方法的基本面。这些工具的现有用户群为11,266个注册用户，他们已经使用并信任我们的软件。该用户基构成了Advaita的独特资产。我们设想的产品将具有许多独特的功能，包括：i）考虑特定基因之间的相互作用； ii）计算一个独特的“影响因子”，该因子表征了生物体的给定子系统在给定条件下的影响； iii）找到疾病和药物作用的机制； iv）查明最佳治疗干预的潜在点；和v）通过监测大量参数（基因表达水平，代谢产物等）来检测生物体中的质量变化。该产品具有以下潜力：i）通过提供较少但更好的候选药物来缩短药物开发周期，ii）帮助了解疾病和药物机制，iii）检测生物生物体的质量变化。该分析方法的科学有效性已在许多应用程序中的真实数据上进行了验证（其中一些已发表，其他描述为初步结果）。在36,000多个基准试验中证明了技术可行性。通过实施包括上述功能的前2个原型，该产品的商业有效性已得到验证。尽管它仅实现了最终功能的一小部分，并且尽管这些客户已经可以访问我们的竞争对手提供的软件产品，但该原型已经出售给了3个客户。 公共卫生相关性：拟议研究的好处预计将影响从癌症到肥胖，衰老到衰老的许多研究领域以及使用高通量方法的任何其他生命科学领域（例如，使用DNA微阵列，蛋白质微阵列，蛋白质微阵列，代谢组学等）。可以从这项研究中受益的生物用户社区包括任何生命科学研究人员，都使用任何生物领域和任何生物体中的高通量方法，从酵母到果蝇，到小鼠到人类。