Biomarkers of Hepatotoxicity in Women Living with HIV and Latent TB
女性艾滋病毒感染者和潜伏性结核病患者的肝毒性生物标志物
基本信息
- 批准号:10013512
- 负责人:
- 金额:$ 14.72万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-04-15 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:AcetyltransferaseAcidsAddressAdultAreaBiological MarkersBiometryCharacteristicsClinicalClinical PharmacologyClinical TrialsClinical Trials NetworkComplementDataDevelopmentDrug KineticsEarly DiagnosisEarly treatmentEnsureEnzymesFoundationsGestational AgeGoalsHIVHIV/TBHealthHelper-Inducer T-LymphocyteHepatotoxicityHumanImmuneImmunologic MarkersImmunologicsImmunologyIndividualInflammatoryInflammatory ResponseInternationalInternational Maternal Pediatric Adolescent AIDS Clinical TrialsKidneyKnowledgeLaboratoriesLinkLiteratureLogistic RegressionsMaternal MortalityMeasuresMediatingMentorsMetabolicModelingOutcomeParentsPatientsPharmaceutical PreparationsPharmacogeneticsPharmacologyPhasePhysiologicalPopulationPostpartum PeriodPostpartum WomenPredictive ValuePregnancyPregnant WomenPrevalencePreventive therapyRegimenResearchResearch PersonnelResearch PrioritySafetySamplingSiteTestingToxic effectTrainingTuberculosisUnited States National Institutes of HealthVulnerable PopulationsWomanWorkWorld Health Organizationadverse drug reactionbasebiomarker developmentcareercase controlcell typecohortcytokinedesigneffective therapyexperienceglomerular filtrationhigh riskimmune functioninfant morbidity/mortalityinsightinterestisoniazidliver injurymaternal morbiditymetabolic phenotypemetabolomicsmortalitynamed grouppreventresponsestatisticstreatment armtuberculosis treatmentuptake
项目摘要
Project Summary & Abstract
Pregnant and postpartum women living with HIV (WLWH) and latent tuberculosis (TB) infection (LTBI) are at
high risk of progressing to active TB. Safe and effective treatment during the latent phase is critical to
preventing active TB, in addition to reducing TB-related maternal and infant morbidity and mortality. Isoniazid
(INH) has been used for decades to treat active and latent TB infection, and there are several international
efforts to expand the use of INH preventive therapy (IPT) to address global TB burden. A recent large-scale
clinical trial in pregnant and postpartum WLWH revealed high rates of severe hepatotoxicity with IPT (~6-7%
vs. <1% based on historical data in non-pregnant adults) during the postpartum period (IMPAACT P1078).
Available evidence suggests reactive INH metabolites are involved in the development of hepatotoxicity with
INH. However, there are currently no data on the pharmacokinetics of INH metabolites in pregnant or
postpartum women. Additionally, there are immunologic and metabolic changes that occur during and after
pregnancy, which may further predispose this population to a higher risk of developing hepatotoxicity during
the postpartum period. Mechanistic insights are needed to inform the safe use of IPT in this population.
This proposal will leverage existing samples collected under the P1078 study to comprehensively examine PK,
immunologic, and metabolic changes in pregnant and postpartum WLWH on IPT using a case-control design.
The following aims are proposed: (1) to quantify INH metabolite PK in pregnant and postpartum WLWH
receiving IPT, (2) to identify biomarkers of hepatotoxicity in pregnant and postpartum WLWH receiving IPT,
and (3) to model relationships between INH metabolite exposures, toxicity biomarkers, and the development of
hepatotoxicity. In Aim 1, INH metabolites will be measured from intensive and sparse PK samples to quantify
INH metabolite PK in pregnant and postpartum women. In Aim 2, an enriched case-control design will be
applied to evaluate baseline and on-treatment biomarkers of hepatotoxicity using metabolomics and cytokine
arrays. Aim 3 will integrate data generated from Aims 1 and 2 to examine relationships between INH
metabolite exposures, metabolic and immunology biomarkers, and the development of hepatotoxicity. This
work will be complemented by a mentoring team comprised of experts in pharmacology, metabolomics,
immunology, and statistics, in addition to collaborators from the P1078 study. Dr. Brooks will also pursue
focused training and coursework in biostatistics, PK modeling, metabolomics, and hands-on experience in the
laboratory setting.
Dr. Brooks's career goal is to become an expert in the clinical pharmacology of TB medications and
mechanisms of immune-mediated adverse drug reactions. The proposed work in Dr. Brooks's K08 application
will provide her with a strong foundation to develop into an independent investigator in this field. Furthermore,
this work will address critical knowledge gaps in a vulnerable population to help support the safe uptake and
expansion of TB preventive therapies on a global scale.
项目概要和摘要
感染艾滋病毒(WLWH)和潜伏性结核病(TB)感染(LTBI)的孕妇和产后妇女在
发展为活动性结核病的风险很高。在潜伏期进行安全有效的治疗,
预防活动性结核病,以及减少与结核病有关的孕产妇和婴儿发病率和死亡率。异烟肼
(INH)几十年来一直用于治疗活动性和潜伏性结核病感染,
努力扩大异烟肼预防性治疗(IPT)的使用,以应对全球结核病负担。近期大规模
妊娠期和产后WLWH的临床试验显示,IPT的严重肝毒性发生率较高(约6-7%),
vs. <1%,基于非妊娠成人的历史数据)在产后期间(IMPAACT P1078)。
现有证据表明,反应性INH代谢产物参与肝毒性的发展,
INH.然而,目前还没有关于INH代谢物在妊娠或哺乳期妇女中的药代动力学数据。
产后妇女。此外,在治疗期间和治疗后,
妊娠,这可能进一步使该人群在妊娠期间发生肝毒性的风险更高。
产后时期。需要机制性的见解来告知在该人群中安全使用IPT。
本提案将利用P1078研究中收集的现有样本,全面检查PK,
免疫和代谢的变化,妊娠和产后WLWH的IPT使用病例对照设计。
本研究的主要目的是:(1)定量测定妊娠期和产后WLWH患者INH代谢产物的PK
(2)鉴定妊娠期和产后接受IPT的WLWH的肝毒性生物标志物,
以及(3)建立INH代谢物暴露、毒性生物标志物和
肝毒性在目标1中,将从密集和稀疏PK样本中测量INH代谢物,以定量
孕妇和产后妇女中的INH代谢物PK。在目标2中,将采用丰富的病例对照设计,
应用代谢组学和细胞因子评价肝毒性的基线和治疗中生物标志物
阵目标3将整合目标1和目标2生成的数据,以检查INH与
代谢物暴露、代谢和免疫学生物标志物以及肝毒性的发展。这
工作将由一个由药理学,代谢组学,
免疫学和统计学,以及来自P1078研究的合作者。布鲁克斯博士还将继续
生物统计学、PK建模、代谢组学方面的重点培训和课程,以及
实验室设置。
博士布鲁克斯的职业目标是成为结核病药物临床药理学方面的专家,
免疫介导的药物不良反应机制。布鲁克斯博士K 08申请中的拟议工作
这将为她发展成为该领域的独立调查员奠定坚实的基础。此外,委员会认为,
这项工作将解决弱势群体的关键知识差距,以帮助支持安全摄取,
在全球范围内推广结核病预防疗法。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Kristina Marie Brooks其他文献
Kristina Marie Brooks的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Kristina Marie Brooks', 18)}}的其他基金
Predictive Power of PEth for HIV Prevention in the Long-Acting Era
PEth 对长效时代 HIV 预防的预测能力
- 批准号:
10542232 - 财政年份:2022
- 资助金额:
$ 14.72万 - 项目类别:
Predictive Power of PEth for HIV Prevention in the Long-Acting Era
PEth 对长效时代 HIV 预防的预测能力
- 批准号:
10693329 - 财政年份:2022
- 资助金额:
$ 14.72万 - 项目类别:
Biomarkers of Hepatotoxicity in Women Living with HIV and Latent TB
女性艾滋病毒感染者和潜伏性结核病患者的肝毒性生物标志物
- 批准号:
10596113 - 财政年份:2020
- 资助金额:
$ 14.72万 - 项目类别:
Biomarkers of Hepatotoxicity in Women Living with HIV and Latent TB
女性艾滋病毒感染者和潜伏性结核病患者的肝毒性生物标志物
- 批准号:
10363663 - 财政年份:2020
- 资助金额:
$ 14.72万 - 项目类别:
相似国自然基金
具有抗癌活性的天然产物金霉酸(Aureolic acids)全合成与选择性构建2-脱氧糖苷键
- 批准号:22007039
- 批准年份:2020
- 资助金额:24.0 万元
- 项目类别:青年科学基金项目
海洋放线菌来源聚酮类化合物Pteridic acids生物合成机制研究
- 批准号:
- 批准年份:2019
- 资助金额:10.0 万元
- 项目类别:省市级项目
手性Lewis Acids催化的分子内串联1,5-氢迁移/环合反应及其在构建结构多样性手性含氮杂环化合物中的应用
- 批准号:21372217
- 批准年份:2013
- 资助金额:80.0 万元
- 项目类别:面上项目
对空气稳定的新型的有机金属Lewis Acids催化剂制备、表征与应用研究
- 批准号:21172061
- 批准年份:2011
- 资助金额:30.0 万元
- 项目类别:面上项目
钛及含钛Lewis acids促臭氧/过氧化氢体系氧化性能的广普性、高效性及其机制
- 批准号:21176225
- 批准年份:2011
- 资助金额:60.0 万元
- 项目类别:面上项目
基于Zip Nucleic Acids引物对高度降解和低拷贝DNA检材的STR分型研究
- 批准号:81072511
- 批准年份:2010
- 资助金额:31.0 万元
- 项目类别:面上项目
海洋天然产物Makaluvic acids 的全合成及其对南海鱼虱存活的影响
- 批准号:30660215
- 批准年份:2006
- 资助金额:21.0 万元
- 项目类别:地区科学基金项目
相似海外基金
Lipid nanoparticle-mediated Inhalation delivery of anti-viral nucleic acids
脂质纳米颗粒介导的抗病毒核酸的吸入递送
- 批准号:
502577 - 财政年份:2024
- 资助金额:
$ 14.72万 - 项目类别:
CAREER: Highly Rapid and Sensitive Nanomechanoelectrical Detection of Nucleic Acids
职业:高度快速、灵敏的核酸纳米机电检测
- 批准号:
2338857 - 财政年份:2024
- 资助金额:
$ 14.72万 - 项目类别:
Continuing Grant
Double Incorporation of Non-Canonical Amino Acids in an Animal and its Application for Precise and Independent Optical Control of Two Target Genes
动物体内非规范氨基酸的双重掺入及其在两个靶基因精确独立光学控制中的应用
- 批准号:
BB/Y006380/1 - 财政年份:2024
- 资助金额:
$ 14.72万 - 项目类别:
Research Grant
Quantifying L-amino acids in Ryugu to constrain the source of L-amino acids in life on Earth
量化 Ryugu 中的 L-氨基酸以限制地球生命中 L-氨基酸的来源
- 批准号:
24K17112 - 财政年份:2024
- 资助金额:
$ 14.72万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Synthetic analogues based on metabolites of omega-3 fatty acids protect mitochondria in aging hearts
基于 omega-3 脂肪酸代谢物的合成类似物可保护衰老心脏中的线粒体
- 批准号:
477891 - 财政年份:2023
- 资助金额:
$ 14.72万 - 项目类别:
Operating Grants
Metabolomic profiles of responders and non-responders to an omega-3 fatty acids supplementation.
对 omega-3 脂肪酸补充剂有反应和无反应者的代谢组学特征。
- 批准号:
495594 - 财政年份:2023
- 资助金额:
$ 14.72万 - 项目类别:
Molecular recognition and enantioselective reaction of amino acids
氨基酸的分子识别和对映选择性反应
- 批准号:
23K04668 - 财政年份:2023
- 资助金额:
$ 14.72万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Integrated understanding and manipulation of hypoxic cellular functions by artificial nucleic acids with hypoxia-accumulating properties
具有缺氧累积特性的人工核酸对缺氧细胞功能的综合理解和操纵
- 批准号:
23H02086 - 财政年份:2023
- 资助金额:
$ 14.72万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Basic research toward therapeutic strategies for stress-induced chronic pain with non-natural amino acids
非天然氨基酸治疗应激性慢性疼痛策略的基础研究
- 批准号:
23K06918 - 财政年份:2023
- 资助金额:
$ 14.72万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Molecular mechanisms how arrestins that modulate localization of glucose transporters are phosphorylated in response to amino acids
调节葡萄糖转运蛋白定位的抑制蛋白如何响应氨基酸而被磷酸化的分子机制
- 批准号:
23K05758 - 财政年份:2023
- 资助金额:
$ 14.72万 - 项目类别:
Grant-in-Aid for Scientific Research (C)