Mentoring of multidisciplinary global health research in tuberculosis and HIV

指导结核病和艾滋病毒多学科全球健康研究

• 批准号: 10431887
• 负责人: James C M Brust
• 金额: $ 17.78万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-02 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10431887
• 关键词: Alveolar Macrophages; Animals; Area; Award; Binding Proteins; Biological Assay; Blood Cells; Caring; Cause of Death; Clinical; Clinical Investigator; Clinical Pharmacology; Clinical Research; Clinical Trials; Collaborations; Communicable Diseases; Companions; Data; Development; Disease; Doctor of Medicine; Dose; Drug Exposure; Drug Kinetics; Drug resistance; Drug resistance in tuberculosis; Early treatment; Effectiveness; Enrollment; Environment; Epidemic; Epidemiology; Extreme drug resistant tuberculosis; Fellowship; Funding; Future; Genomics; Goals; HIV; HIV/TB; Half-Life; Hour; Human; Individual; Institution; Interdisciplinary Study; Intermediate resistance; International; Interruption; Kinetics; Knowledge; Leprosy; Linezolid; Lung; Measurement; Measures; Medicine; Mentors; Mentorship; Meta-Analysis; Microbiology; Mid-Career Clinical Scientist Award (K24); Modeling; Multidrug-Resistant Tuberculosis; Mycobacterium tuberculosis; Participant; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacology; Physicians; Plasma; Population; Postdoctoral Fellow; Prevention; Recommendation; Regimen; Research; Research Personnel; Resistance; Rifampicin resistance; Risk; Scientist; Site; South Africa; Specialist; Structure; Survival Rate; Therapeutic Index; Time; Training; Treatment Protocols; Treatment outcome; Tuberculosis; career; cell type; clinical training; college; design; epidemiology study; extensive drug resistance; genome sequencing; global health; improved; innovation; interest; medical schools; mortality; multidisciplinary; next generation; novel; novel therapeutics; pathogen; patient oriented research; pre-doctoral; premature; programs; skills; success; tandem mass spectrometry; translational study; tuberculosis drugs; tuberculosis treatment; whole genome

PROJECT SUMMARY Dr. Brust is an infectious diseases specialist and physician-scientist at Albert Einstein College of Medicine. His multidisciplinary patient-oriented research (POR) program focuses on the interplay of tuberculosis (TB) and HIV in South Africa. A K24 Award would allow him to expand his POR program and develop a robust mentoring program in TB, HIV and global health research at Einstein. Worldwide, TB is the most common cause of death in patients with HIV, and the growing epidemic of drug-resistance threatens decades of gains in TB prevention and care. With an emerging pipeline of novel and repurposed TB medications, there is an urgent need for innovative research in TB pharmacology, genomics, and clinical trials to evaluate these drugs. Similarly, there is a need to train the next generation of scientists in multidisciplinary TB/HIV and global health POR. Dr. Brust's research program of clinical, epidemiologic, and translational studies is built upon a network of outstanding collaborators in pharmacology, genomics, microbiology and epidemiology. He has a strong record of successfully mentoring pre-and post-doctoral trainees from multiple institutions and using his collaborators to provide mentees with broad technical and professional expertise. Einstein has a rich environment for training clinical investigators through its medical school, post-doctoral fellowships and multi- disciplinary centers (CTSA, CFAR, Global Health). Within this highly conducive training environment and with a multi-institutional and multinational collaborative research team, Dr. Brust can expand his comprehensive mentoring program at Einstein and internationally. His research program is unique at Einstein and his mentorship is sought by trainees and junior investigators. His mentorship focuses on the design and execution of hypothesis-driven research to assist mentees in becoming independent investigators. By allowing him to decrease his clinical responsibilities, this K24 award will permit him to devote more time to mentorship and to take on a larger number of mentees. The award will also advance his immediate and long-term career goals to: 1) Increase his knowledge of clinical pharmacology to inform current and future studies of new TB medications; 2) Understand how whole genome sequencing can reveal mechanisms of acquired TB resistance; 3) Expand clinical trials skills to facilitate the design and implementation of TB/HIV trials for novel drugs; and 4) Enhance the structure and content of his mentorship of trainees pursuing careers in TB/HIV and global health POR. Finally, this award will support an innovative sub-study of Dr. Brust's new R01 to further investigate the TB drug clofazimine: 1) To develop a novel assay to measure intracellular clofazimine concentrations; 2) To correlate intracellular clofazimine concentrations with the emergence of bedaquiline resistance following a treatment interruption; and 3) to compare intracellular clofazimine concentrations in alveolar macrophages with that in PBMCs. A K24 award will provide vital protected time, enabling Dr. Brust to build upon his current success and giving him the skills to grow as both an investigator and as a mentor.

项目摘要 博士布鲁斯特是阿尔伯特·爱因斯坦医学院的传染病专家和医生科学家。他 多学科以患者为导向的研究（POR）计划的重点是结核病（TB）和 艾滋病在南非K24奖将使他能够扩大他的POR计划，并制定一个强大的 在结核病，艾滋病和全球健康研究爱因斯坦导师计划。在世界范围内，结核病是最常见的 艾滋病毒感染者的死亡原因，以及日益严重的耐药性流行威胁着几十年来在艾滋病领域取得的进展。 结核病预防和护理。随着新型和重新用途的结核病药物的出现， 需要在结核病药理学、基因组学和临床试验方面进行创新研究，以评估这些药物。 同样，需要在结核病/艾滋病毒和全球卫生多学科领域培训下一代科学家 POR。布鲁斯特博士的临床，流行病学和转化研究的研究计划是建立在一个网络 药理学、基因组学、微生物学和流行病学领域的杰出合作者。他有很强 成功指导来自多个机构的博士前和博士后学员的记录，并利用他的 合作伙伴，为学员提供广泛的技术和专业知识。爱因斯坦有丰富的 通过其医学院，博士后奖学金和多学科培训临床研究人员的环境， 学科中心（CTSA，CFAR，全球健康）。在这种非常有利的培训环境中， 多机构和跨国合作研究团队，布鲁斯特博士可以扩大他的全面 在爱因斯坦和国际上的指导计划。他的研究计划在爱因斯坦和他的 学员和初级调查员寻求指导。他的指导重点是设计和执行 假设驱动的研究，以帮助学员成为独立的调查员。通过允许他 减少他的临床责任，这个K24奖将使他能够投入更多的时间来指导和 接纳更多的学员。该奖项还将推进他的近期和长期职业目标： 1)增加临床药理学知识，为当前和未来的结核病新药研究提供信息; 2)了解全基因组测序如何揭示获得性结核病耐药性的机制; 3）扩大 临床试验技能，以促进结核病/艾滋病毒新药试验的设计和实施;以及4）加强 他对在结核病/艾滋病和全球卫生POR领域寻求职业生涯的学员的指导的结构和内容。 最后，该奖项将支持Brust博士的新R 01的创新子研究，以进一步研究结核病 药物氯法齐明：1）开发一种新的测定细胞内氯法齐明浓度的方法; 2） 细胞内氯法齐明浓度与贝达喹啉耐药性的出现相关， 治疗中断;和3）比较肺泡巨噬细胞中的细胞内氯法齐明浓度， 在PBMC中。K24奖将提供重要的保护时间，使布鲁斯特博士能够在他目前的基础上 成功，并给他的技能，成长为一个调查员和导师。

项目成果

Model-Predicted Impact of ECG Monitoring Strategies During Bedaquiline Treatment.

• DOI: 10.1093/ofid/ofac372
• 发表时间: 2022-08
• 期刊: Open forum infectious diseases
• 影响因子: 4.2

Effectiveness and Cardiac Safety of Bedaquiline-Based Therapy for Drug-Resistant Tuberculosis: A Prospective Cohort Study.

• DOI: 10.1093/cid/ciab335
• 发表时间: 2021-12-06
• 期刊: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
• 作者: Brust JCM;Gandhi NR;Wasserman S;Maartens G;Omar SV;Ismail NA;Campbell A;Joseph L;Hahn A;Allana S;Hernandez-Romieu AC;Zhang C;Mlisana K;Viljoen CA;Zalta B;Ebrahim I;Franczek M;Master I;Ramangoaela L;Te Riele J;Meintjes G
• 通讯作者: Meintjes G

Clofazimine pharmacokinetics in patients with TB: dosing implications.

• DOI: 10.1093/jac/dkaa310
• 发表时间: 2020-11-01
• 期刊: The Journal of antimicrobial chemotherapy
• 作者: Abdelwahab MT;Wasserman S;Brust JCM;Gandhi NR;Meintjes G;Everitt D;Diacon A;Dawson R;Wiesner L;Svensson EM;Maartens G;Denti P
• 通讯作者: Denti P

Linezolid toxicity in patients with drug-resistant tuberculosis: a prospective cohort study.

• DOI: 10.1093/jac/dkac019
• 发表时间: 2022-03-31
• 期刊: The Journal of antimicrobial chemotherapy
• 作者: Wasserman S;Brust JCM;Abdelwahab MT;Little F;Denti P;Wiesner L;Gandhi NR;Meintjes G;Maartens G
• 通讯作者: Maartens G

Optimized Loading Dose Strategies for Bedaquiline When Restarting Interrupted Drug-Resistant Tuberculosis Treatment.

重新开始中断的耐药结核病治疗时贝达喹啉的优化负荷剂量策略。

• DOI: 10.1128/aac.01749-21
• 发表时间: 2022
• 期刊: Antimicrobial agents and chemotherapy
• 影响因子: 4.9
• 作者: Koele,SimonE;vanBeek,StijnW;Maartens,Gary;Brust,JamesCM;Svensson,ElinM
• 通讯作者: Svensson,ElinM