Impact of the gut microbiome on response to lipid lowering therapy
肠道微生物组对降脂治疗反应的影响
基本信息
- 批准号:10181026
- 负责人:
- 金额:$ 17.38万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-06-01 至 2023-05-31
- 项目状态:已结题
- 来源:
- 关键词:16S ribosomal RNA sequencingAcidsAddressAftercareAgonistAnimalsBacteriaBacterial GenesBacterial GenomeBile AcidsBioinformaticsCardiacCardiovascular DiseasesCardiovascular systemCause of DeathCholesterolClinicalComplexDataData AnalysesDevelopmentDoseDrug ModelingsDrug TargetingEnvironmentEnzymesEventExposure toFGF19 geneFibroblast Growth Factor ReceptorsFundingGene ClusterGoalsHeart DiseasesHomeostasisHumanHydrolaseIndividualInnovative TherapyInterventionIntervention StudiesKnowledgeLDL Cholesterol LipoproteinsLinkLipidsLow-Density LipoproteinsMentorsMetabolismMetagenomicsMethodologyMethodsMorbidity - disease rateNicotinic AcidsNuclear ReceptorsObservational StudyPathway interactionsPatient-Focused OutcomesPennsylvaniaPharmaceutical PreparationsPharmacological TreatmentPharmacologyPlacebosPlasmaPlayRandomizedResearchResearch InfrastructureResearch InstituteResearch PersonnelResearch TrainingResidual stateRibosomal RNARiskRoleSecondary toSerumSignal TransductionTrainingTraining ProgramsTranslational ResearchUnited States National Institutes of HealthUniversitiesVariantWorkXenobiotic Metabolismbile acid metabolismbile saltscardiogenesiscareer developmentclinically relevantevidence baseexperiencegut bacteriagut microbiomegut microbiotahealthy volunteerheart disease riskhost microbiomehuman modelhuman subjectimprovedimproved outcomeinnovationlipid metabolismmetabolomicsmetagenomic sequencingmicrobiomemicrobiome compositionmicrobiome researchmicrobiotamortalitynew technologynew therapeutic targetnovelpatient orientedpreventreceptorresponseresponse biomarkerrosuvastatinsmall moleculestool sampletreatment response
项目摘要
Project Summary
Despite the availability of evidence-based strategies such as high-dose statins, cardiovascular disease (CVD)
remains the leading cause of death worldwide. Statins effectively reduce plasma low-density lipoprotein
cholesterol (LDL-C) concentrations and prevent cardiovascular events; however, there is a great deal of
variability and inadequate response to statins. Additionally, susceptible individuals continue to experience
cardiac events even while on aggressive statin therapy, referred to as residual risk. Therefore we need to
improve our understanding of the factors contributing to pharmacological variability to statin therapy.
Understanding the variability in pharmacologic treatment and the best strategy for addressing residual risk will
enhance our efforts in decreasing CVD related morbidity and mortality. Accumulating evidence suggests that
intestinal microbiota impacts the development of CVD, host plasma lipid levels, metabolism of xenobiotics, and
has shown to be a contributing factor in drug variability. Importantly, is unknown whether the gut microbiome
impacts the efficacy of statin medications. The objective of this proposal is to understand the interaction
between the gut microbiome and host drug response to statin therapy using 16S rRNA sequencing,
metagenomics sequencing and bile acid metabolomics, as well as provide the applicant with a patient-oriented
mentored training program to gain expertise in metagenomics and metabolomic data interpretation and
analysis. In Aim 1, a placebo-controlled interventional study will be performed in 90 healthy subjects to
determine if rosuvastatin impacts the gut microbiota composition. Stool samples at before and after treatment
will be analyzed by 16S rRNA and metagenomics sequencing. In Aim 2, the contribution of gut-derived bile
acid metabolites and fibroblast growth factor (FGF)-19 to the LDL-C lowering effect of rosuvastatin will be
determined. Stool samples will be analyzed by targeted metabolomic analysis. A career development and
training plan for the applicant is outlined including training in metagenomics and metabolomics methodology
required for completion of this project. The University of Pennsylvania is a world-class research institute and a
wonderful environment for this training and research. This proposal is innovative and unique in that it integrates
human models of drug-induced metagenomics and metabolomic signatures with drug response. A better
understanding of the complex interactions of the gut microbiome with host drug response to statin therapy
could advance our understanding of additional factors contributing to the variability of drug response, identify
poor responders to treatment and inform the development of novel therapeutics for targeting residual risk in
CVD. Most importantly, this research and training will provide the applicant with the means to discover clinically
relevant drug response biomarkers and drug targets that will improve outcomes for patients with CVD.
项目摘要
尽管有循证策略,如高剂量他汀类药物,心血管疾病(CVD)
仍然是世界范围内的主要死因。他汀类药物有效降低血浆低密度脂蛋白
胆固醇(LDL-C)浓度和预防心血管事件;然而,有大量的
变异性和对他汀类药物的反应不足。此外,易感个体继续经历
心脏事件,即使在积极的他汀类药物治疗,称为剩余风险。因此我们需要
提高我们对他汀类药物治疗的药理学变异性的因素的理解。
了解药物治疗的可变性和解决剩余风险的最佳策略将
加强我们在降低心血管疾病相关发病率和死亡率方面的努力。越来越多的证据表明,
肠道微生物群影响CVD的发展、宿主血浆脂质水平、外源性物质的代谢,
已被证明是药物变异性的一个促成因素。重要的是,尚不清楚肠道微生物组是否
影响他汀类药物的疗效。本提案的目的是了解
肠道微生物组和宿主药物对他汀类药物治疗反应之间的关系,
宏基因组学测序和胆汁酸代谢组学,以及为申请人提供以患者为导向的
指导培训计划,以获得宏基因组学和代谢组学数据解释方面的专业知识,
分析.在目标1中,将在90例健康受试者中进行安慰剂对照干预性研究,
确定瑞舒伐他汀是否影响肠道微生物群组成。处理前后的粪便样本
将通过16 S rRNA和宏基因组测序进行分析。在目标2中,肠源性胆汁的贡献
酸性代谢产物和成纤维细胞生长因子(FGF)-19对瑞舒伐他汀降低LDL-C作用的影响将是
测定粪便样本将通过靶向代谢组学分析进行分析。职业发展和
概述了申请人的培训计划,包括宏基因组学和代谢组学方法的培训
完成该项目所需的。宾夕法尼亚大学是世界一流的研究机构,
这是一个很好的环境,为这个培训和研究。这一建议是创新和独特的,因为它整合了
药物诱导的宏基因组学和具有药物反应的代谢组学特征的人类模型。更好的
了解肠道微生物组与宿主药物对他汀类药物治疗反应的复杂相互作用
可以促进我们对导致药物反应变异性的其他因素的理解,
对治疗反应差,并为开发新的治疗方法提供信息,
CVD。最重要的是,这项研究和培训将为申请人提供临床发现的手段,
相关的药物反应生物标志物和药物靶点,将改善CVD患者的结局。
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 }}
Sony Tuteja其他文献
Sony Tuteja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('Sony Tuteja', 18)}}的其他基金
Impact of the gut microbiome on response to lipid lowering therapy
肠道微生物组对降脂治疗反应的影响
- 批准号:
10418776 - 财政年份:2019
- 资助金额:
$ 17.38万 - 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:
$ 17.38万 - 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:
$ 17.38万 - 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:
$ 17.38万 - 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:
$ 17.38万 - 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:
$ 17.38万 - 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:
$ 17.38万 - 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:
$ 17.38万 - 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:
$ 17.38万 - 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:
$ 17.38万 - 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:
$ 17.38万 - 项目类别:
Grant-in-Aid for Scientific Research (C)