Data-driven drug discovery: investigating the molecular mechanisms of safety and efficacy

数据驱动的药物发现：研究安全性和有效性的分子机制

• 批准号: 10625365
• 负责人: Nicholas P Tatonetti
• 金额: $ 35.36万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10625365
• 关键词: Address; Affect; Age; Animal Experimentation; Animal Model; Attention; Behavioral; Biological Models; Cell model; Child; Clinical; Clinical Trials; Couples; Dangerousness; Data; Data Analyses; Data Science; Data Sources; Devices; Drug Design; Drug Interactions; Electronic Health Record; Funding; Gender; Genes; Health; Informatics; Intervention; Knowledge; Longevity; Medical Records; Medicine; Methods; Minority; Modern Medicine; Molecular; Pathway interactions; Patient Rights; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacology Study; Physiological Effects of Drugs; Population Heterogeneity; Privacy; Reaction; Research; Research Personnel; Safety; Science; Vision; Woman; Work; adverse drug reaction; data mining; drug discovery; drug efficacy; experimental study; improved; invention; laboratory experiment; medication safety; molecular modeling; next generation; patient population; pharmacologic; pharmacovigilance; precision medicine; privacy preservation; programs; prospective; sex; side effect; translational medicine

Project Summary I am proposing a precision pharmacology and pharmacovigilance research program that couples observational data analysis with prospective laboratory experiments to advance drug safety and efficacy. Our ability to collect and store massive amounts of molecular, clinical, and behavioral data has the potential to fundamentally transform translational medicine. It is not difficult to imagine a world where our devices and doctors work together seamlessly to provide personalized guidance and treatment to maximize our health and longevity. And that, in turn, the data generated by these encounters be collected, organized, and analyzed by biomedical researchers to invent the next generation of interventions. However, there are significant challenges prohibiting meaningful progress toward this vision. I have identified four that I plan to address: (1) There is a dearth of pharmacological knowledge for many subpopulations, most notably minorities (non-Whites), women, and children; (2) Observational data, from what is captured by devices to what is collected in medical records, is of dubious validity and value; (3) There is a limited understanding of the molecular mechanisms of drug reactions and drug-drug interactions; (4) There is no clear method of meaningfully sharing patient data while preserving privacy. There is no single solution that will solve all of these challenges. Each will require a unique combination of data science, informatics, and experiments. In the previously funded project, we made significant advancements in the characterization of adverse drug reactions and drug-drug interactions, the molecular modeling of pharmacological pathways, and the application of statistical data mining to electronic health records. I accomplished this by leveraging distinct data sources against each other to focus attention on only those hypotheses that repeatedly replicate under a variety of conditions. I then validated those hypotheses experimentally using animal and cellular models. Challenges 2 and 3 are natural extensions of this previous work, where I will address how to use data for purposes other than what it was collected for (secondary use) and develop new systems models to explain the physiological effects of drug-gene and drug-drug interactions. Challenges 1 and 4 represent new avenues of research where I will address the challenges of pharmacological studies in diverse populations and the increasingly important issue of balancing openness and transparency in science with patients' rights to privacy. The challenges laid out above are significant and, likely, will not be solved in within five years. However, the pursuit of these challenges will generate new knowledge that has the potential to significantly improve drug design, advance precision medicine, and guide drug safety governance.

项目摘要 我正在提议一个精确的药理学和药物警戒研究项目，让夫妇观察 通过前瞻性实验室实验进行数据分析，以提高药物的安全性和有效性。我们收集数据的能力 并存储大量的分子、临床和行为数据，有可能从根本上 转变转化医学。不难想象，在我们的设备和医生工作的世界里 天衣无缝地提供个性化的指导和治疗，最大限度地提高我们的健康和长寿。 反过来，由这些相遇产生的数据由生物医学收集、组织和分析 研究人员将发明下一代干预措施。然而，禁止 朝着这一愿景取得了有意义的进展。我已经确定了我计划解决的四个问题： (1)许多亚群缺乏药理知识，尤其是少数族裔 (非白人)、妇女和儿童； (2)观测数据，从设备捕获的数据到医疗记录中收集的数据，都是 有效性和价值令人怀疑； (3)对药物反应和药物-药物的分子机制认识有限。 相互作用； (4)没有明确的方法在保护隐私的同时有意义地共享患者数据。 没有一个单一的解决方案可以解决所有这些挑战。每一项都需要唯一的数据组合 科学、信息学和实验。在之前获得资助的项目中，我们在以下方面取得了重大进展 药物不良反应和药物相互作用的表征、药物的分子模拟 药理途径，以及统计数据挖掘在电子健康记录中的应用。我 这是通过相互利用不同的数据源来实现的，以便只将注意力集中在 在各种条件下反复重复的假设。然后我验证了这些假设 使用动物和细胞模型进行实验。挑战2和挑战3是前两个挑战的自然延伸 工作，在那里我将解决如何将数据用于收集数据以外的目的(二次使用) 并开发新的系统模型来解释药物-基因和药物-药物相互作用的生理效应。 挑战1和挑战4代表了新的研究途径，我将在其中解决药理学的挑战 在不同人群中进行的研究，以及平衡公开和透明的日益重要的问题 科学与患者的隐私权。上面列出的挑战是重大的，很可能不会 在五年内就解决了。然而，对这些挑战的追求将产生新的知识，具有 有潜力显著改进药物设计，推进精准医学，指导药品安全治理。

项目成果

Longitudinal profiling of circulating miRNA during cardiac allograft rejection: a proof-of-concept study.

• DOI: 10.1002/ehf2.13238
• 发表时间: 2021-06
• 期刊: ESC heart failure
• 影响因子: 3.8
• 作者: Kennel PJ;Yahi A;Naka Y;Mancini DM;Marboe CC;Max K;Akat K;Tuschl T;Vasilescu EM;Zorn E;Tatonetti NP;Schulze PC
• 通讯作者: Schulze PC

Structured deep embedding model to generate composite clinical indices from electronic health records for early detection of pancreatic cancer.

• DOI: 10.1016/j.patter.2022.100636
• 发表时间: 2023-01-13
• 期刊: PATTERNS
• 影响因子: 6.5
• 作者: Park, Jiheum;Artin, Michael G.;Lee, Kate E.;May, Benjamin L.;Park, Michael;Hur, Chin;Tatonetti, Nicholas P.
• 通讯作者: Tatonetti, Nicholas P.

Where Have All the Emergencies Gone? The Impact of the COVID-19 Pandemic on Obstetric and Gynecologic Procedures and Consults at a New York City Hospital.

• DOI: 10.1016/j.jmig.2020.11.012
• 发表时间: 2021-07
• 期刊: Journal of minimally invasive gynecology
• 影响因子: 4.1
• 作者: Spurlin EE;Han ES;Silver ER;May BL;Tatonetti NP;Ingram MA;Jin Z;Hur C;Advincula AP;Hur HC
• 通讯作者: Hur HC

No Increased Risk of Colorectal Adenomas in Spouses of Patients with Colorectal Neoplasia.

结直肠肿瘤患者的配偶患结直肠腺瘤的风险不会增加。

• DOI: 10.1016/j.cgh.2019.03.038
• 发表时间: 2020
• 期刊: Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association
• 作者: Krigel,Anna;Tatonetti,NicholasP;Neugut,AlfredI;Lebwohl,Benjamin
• 通讯作者: Lebwohl,Benjamin

Association of Neighborhood Deprivation Index With Success in Cancer Care Crowdfunding.

• DOI: 10.1001/jamanetworkopen.2020.26946
• 发表时间: 2020-12-01
• 期刊: JAMA network open
• 影响因子: 13.8
• 作者: Silver ER;Truong HQ;Ostvar S;Hur C;Tatonetti NP
• 通讯作者: Tatonetti NP