Chemoinformatics Core

化学信息学核心

• 批准号: 10448342
• 负责人: Thomas Girke
• 金额: $ 81.36万
• 依托单位: CALIFORNIA PACIFIC MED CTR RES INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10448342
• 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; System; Testing; Validation; analog; base; biological systems; combinatorial; cost; data dissemination; data integration; data sharing; drug candidate; drug repurposing; experimental study; gene expression database; 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; web portal

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长寿相关药物和目标蛋白 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）。这些协会将有效利用大量的药物靶点 公共领域可用的相互作用数据，包括现有药物的高质量注释、高质量 涉及药物治疗的通量生物测定和基因表达数据。目标 1 将系统地评估 根据目前的数据，哪些与长寿 MOH 组相关的蛋白质会受到药物的干扰 可在公共参考数据库中找到。目标 2 将鉴定诱导类似基因表达变化的药物 那些与健康老龄化和长寿相关的人。目标 3 将整合蛋白质家族信息 使用生物活性信息补偿某些感兴趣的蛋白质生物测定信息的缺乏 可用于生物体内部和生物体之间密切相关的蛋白质。目标 4 将优先考虑候选药物 他们的实验证据水平、注释和选择性水平，以及它们的有用潜力 通过调节蛋白质的活性来进行药物再利用方法或组合策略 多种选择性药物或针对多种蛋白质的单一药物的感兴趣途径。目标5将 使用实验验证已确定的候选药物对长寿和健康老龄化的影响 米勒小鼠/细胞项目的筛选程序。通过这些验证测试的候选药物将 与 LC 和外部咨询委员会成员进一步评估下游转化研究。 此外，将与长寿药物靶点网络密切合作进行计算和询问。 Schork 疾病背景、Orwoll 蛋白质组学、Fiehn 代谢组学和 Perls 百岁老人项目， 和价格系统核心。目标6将整理、整合和共享所有分析结果和软件 由 LC 通过开发 LC 数据库 (LCDB) 门户与公众共同开发。分析方法 由 Girke-chemoinformatics 核心开发的项目将作为 R 包发布在 GitHub 上， 生物导体。初步数据和机密数据将保留在 LCDB 的私人领域，而所有其他数据 将被公开。总之，Girke 确定的药物靶点和药物特征对 化学信息学核心将有可能为转化方法提供新的线索 推进长寿研究。如果成功，他们将实现创新药理学策略 开发药物或食品补充剂以促进人类健康老龄化和长寿。详细证明 已经进行了概念实验，并与其他项目一起进行了综合试点研究 项目和核心团队。从这些实验中获得的大量积极结果表明 该方法成功的可能性很高。