Chemoinformatics Core

化学信息学核心

• 批准号: 9788195
• 负责人: Thomas Girke
• 金额: $ 31.92万
• 依托单位: CALIFORNIA PACIFIC MED CTR RES INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9788195
• 关键词: Address; Advisory Committees; Affect; Algorithms; Amino Acid Sequence; Anabolism; Bioconductor; Biological Assay; Biological Process; Cell Line; Cells; Centenarian; Collaborations; Committee Members; Communities; Data; Data Analyses; Databases; Disease; Drug Targeting; Food Supplements; Gene Expression; Gene Expression Profile; Genes; Genetic; Goals; Human; Knowledge; Link; Longevity; Maps; Methods; Modeling; Molecular; Mus; Organism; Orthologous Gene; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Pilot Projects; Positioning Attribute; Price; Privatization; Process; Protein Family; Proteins; Proteome; Proteomics; Public Domains; Publishing; Reproducibility; Research; Structure; System; Testing; Validation; analog; base; biological systems; combinatorial; cost; data integration; data sharing; drug candidate; experimental study; genetic variant; healthy aging; innovation; interest; member; metabolomics; multiple omics; novel; protein metabolite; screening; screening program; small molecule; software development; success; transcriptome sequencing; transcriptomics; translational approach; translational study

The Girke-chemoinformatics core will identify longevity-associated drugs and target proteins for the genetic and molecular findings (here multi-omics hits, MOH) discovered by the other projects and cores of the Longevity Consortium (LC). These associations will make efficient use of the large body of drug-target interaction data available in the public domain including high-quality annotations of existing drugs, high- throughput bioassays and gene expression data involving drug treatments. Aim 1 will systematically assess which proteins associated with longevity MOH sets are perturbable by drugs given the data currently available in public reference databases. Aim 2 will identify drugs inducing gene expression changes similar to those associated with healthy aging and longevity. Aim 3 will incorporate protein family information to compensate for the lack of bioassay information for certain proteins of interest using bioactivity information available for closely related proteins within and across organisms. Aim 4 will prioritize drug candidates by their level of experimental evidence, annotation and selectivity levels, as well as their potential to be useful for drug repurposing approaches or combinatorial strategies by modulating the activity of proteins in pathways of interest with several selective drugs or single drugs targeting multiple proteins. Aim 5 will validate the effects of the identified drug candidates on longevity and healthy aging using the experimental screening program of the Miller-mice/cells project. Candidate drugs passing these validation tests will be further evaluated for downstream translational studies with LC and external advisory committee members. Moreover, longevity drug-target networks will be computed and interrogated in close collaboration with the Schork-disease context, Orwoll-proteomics, Fiehn-metabolomics and Perls-centenarian projects, and the Price-systems core. Aim 6 will organize, integrate and share all analysis results and software developed by the LC with the public by developing the LC database (LCDB) portal. Analysis methods developed by the Girke-chemoinformatics core will be published as R packages on GitHub and Bioconductor. Preliminary and confidential data will remain in LCDB’s private domain, while all other data will be publicly available. In summary, the drug-target and drug-signature pairs identified by the Girke- chemoinformatics core will have the potential of providing novel leads for translational approaches advancing longevity research. If successful, they will enable innovative pharmacological strategies of developing drugs or food supplements for enhancing healthy aging and longevity in humans. Detailed proof of concept experiments have been performed, as well as an integrated pilot study together with the other project and core teams. The large number of positive results obtained from these experiments demonstrate the high likelihood of success of the approach.

Girke化学信息学核心将识别与长寿相关的药物和目标蛋白质 其他项目和核心发现的遗传和分子发现(这里是多组学命中，MOH) 长寿联盟(LC)。这些协会将有效地利用大量的药物靶标 公共领域中可用的交互数据，包括现有药物的高质量注释、高质量 包括药物治疗的生物检测和基因表达数据。目标1将系统地评估 根据目前的数据，哪些与长寿MOH相关的蛋白质可以被药物干扰 可在公共参考数据库中使用。目标2将识别引起类似基因表达变化的药物 那些与健康衰老和长寿有关的人。AIM 3将结合蛋白质家族信息 利用生物活性信息弥补某些感兴趣蛋白质的生物测定信息的缺乏 可用于生物体内和生物体之间密切相关的蛋白质。AIM 4将通过以下方式对候选药物进行优先排序 它们的实验证据水平、注释和选择性水平以及它们的有用潜力 用于药物再利用的方法或组合策略通过调节蛋白质的活性 针对多个蛋白质的几种选择性药物或单一药物的感兴趣途径。目标5将 通过实验验证已确定的候选药物对长寿和健康衰老的影响 米勒-小鼠/细胞项目的筛选计划。通过这些验证测试的候选药物将是 进一步评估与LC和外部咨询委员会成员进行的下游翻译研究。 此外，将与联合国毒品和犯罪问题办公室密切合作，计算和审问长寿药物目标网络。 Schork病背景、Orwoll蛋白质组学、Fiehn代谢组学和Perls-百年计划， 以及价格系统的核心。AIM 6将组织、集成和共享所有分析结果和软件 由立法会通过开发立法会数据库(LCDB)门户网站与公众共同开发。分析方法 由Girke开发的化学信息学核心将以R包的形式在GitHub和 生物导体。初步和机密数据将保留在LCDB的私域中，而所有其他数据 将向公众开放。总而言之，Girke确定的药物靶标和药物签名对- 化学信息学核心将有可能为翻译方法提供新的线索 推进长寿研究。如果成功，它们将使创新的药理学策略成为可能 开发药物或食品补充剂，以促进人类的健康衰老和长寿。详细的证明 进行了大量的概念实验，并与另一个 项目和核心团队。从这些实验中获得的大量积极结果表明 这种方法成功的可能性很高。