Improving CPT-11 Efficacy Using Structural and Chemical Biology
利用结构生物学和化学生物学提高 CPT-11 功效
基本信息
- 批准号:9326146
- 负责人:
- 金额:$ 26.39万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-09-23 至 2019-08-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAddressAdverse effectsAnimalsAnti-Inflammatory AgentsAnti-inflammatoryAntineoplastic AgentsApplied ResearchBacteriaBasic ScienceBeta-glucuronidaseBindingBiologicalBiologyCamptothecin-11Cell DeathChemicalsChemotherapy-Oncologic ProcedureColorectal CancerDiarrheaDose-LimitingEnteralEnzymesEpithelial CellsGlucuronic AcidsGlucuronidase InhibitorGoalsHealthHumanIn VitroIntestinesKnowledgeMalignant NeoplasmsMalignant neoplasm of pancreasMammalian CellMetagenomicsMolecularOralPharmaceutical ChemistryPharmaceutical PreparationsPharmacologyProteinsReagentResearchScienceStructural BiochemistryStructureSugar AcidsSymbiosisTestingTherapeuticTimeToxic effectUlcerdeep sequencingdesignenzyme activitygut microbiomegut microbiotaimprovedimproved outcomeinhibitor/antagonistirinotecanmicrobialmicrobiomemicrobiotamouse modelmutualismnovelnovel therapeuticspublic health relevancestructural biologytherapeutic enzymetool
项目摘要
DESCRIPTION (provided by applicant): We are alleviating the toxicity of the anticancer drug CPT-11 by modulating components of the GI microbiome. CPT-11 is essential in treating colorectal and pancreatic cancer, but dose-limiting toxicity severely reduces its efficacy. This toxicity is caused by a bacterial enzyme in enteric microbial symbiotes. The enzyme, ß-glucuronidase, removes the inactivating glucuronic acid sugar from CPT-11's key metabolite, which reactivates the drug in the GI and produces epithelial cell death and acute diarrhea. We hypothesized that the selective, non-lethal inhibition of microbial ß-glucuronidases would alleviate this side effect. This hypothesis tested true in proof-of-concept molecular-to-animal studies conducted in the previous project period. We will now advance the project in three crucial ways. First, we will characterize the range of active ß-glucuronidases present in the GI microbiome using structural biology and biochemistry. Second, we will create differentially optimized bacterial ß-glucuronidase inhibitors via structural and chemical biology. Third, using deep-sequencing and metagenomics, we will unravel how this approach impacts the composition and activity of the GI microbiome. In summary, we seek to advance a novel paradigm - inhibiting specific microbial enzymes for therapeutic gain without harming the bacterial symbiotes essential for human health.
描述(由申请人提供):我们正在通过调节GI微生物组的组分来减轻抗癌药物CPT-11的毒性。CPT-11在治疗结直肠癌和胰腺癌方面至关重要,但剂量限制性毒性严重降低了其疗效。这种毒性由肠道微生物共生体中的细菌酶引起。这种酶,β-葡萄糖醛酸酶,从CPT-11的关键代谢物中去除失活的葡萄糖醛酸糖,这会在胃肠道中重新激活药物,并产生上皮细胞死亡和急性腹泻。我们假设选择性的、非致死性的抑制微生物β-葡萄糖醛酸苷酶可以减轻这种副作用。这一假设在前一个项目期间进行的概念验证分子到动物研究中得到了验证。我们现在将从三个关键方面推进该项目。首先,我们将使用结构生物学和生物化学表征GI微生物组中存在的活性β-葡萄糖醛酸苷酶的范围。其次,我们将通过结构和化学生物学创建差异优化的细菌β-葡萄糖醛酸酶抑制剂。第三,使用深度测序和宏基因组学,我们将揭示这种方法如何影响GI微生物组的组成和活性。总之,我们寻求推进一种新的范式-抑制特定的微生物酶以获得治疗效果,而不损害对人类健康至关重要的细菌共生体。
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 }}
Matthew R Redinbo其他文献
Matthew R Redinbo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('Matthew R Redinbo', 18)}}的其他基金
Understanding and Controlling Drug Metabolism by the Gut Microbiota to Improve Human Health
了解和控制肠道微生物群的药物代谢以改善人类健康
- 批准号:
10401799 - 财政年份:2020
- 资助金额:
$ 26.39万 - 项目类别:
Understanding and Controlling Drug Metabolism by the Gut Microbiota to Improve Human Health
了解和控制肠道微生物群的药物代谢以改善人类健康
- 批准号:
10616518 - 财政年份:2020
- 资助金额:
$ 26.39万 - 项目类别:
Structural Basis for Hormone and Neurotransmitter Processing by Gut Microbial Enzymes
肠道微生物酶处理激素和神经递质的结构基础
- 批准号:
10438768 - 财政年份:2019
- 资助金额:
$ 26.39万 - 项目类别:
Structural Basis for Hormone and Neurotransmitter Processing by Gut Microbial Enzymes
肠道微生物酶处理激素和神经递质的结构基础
- 批准号:
10205109 - 财政年份:2019
- 资助金额:
$ 26.39万 - 项目类别:
Structural Basis for Hormone and Neurotransmitter Processing by Gut Microbial Enzymes
肠道微生物酶处理激素和神经递质的结构基础
- 批准号:
10019410 - 财政年份:2019
- 资助金额:
$ 26.39万 - 项目类别:
Improving CPT-11 Efficacy Using Structural and Chemical Biology
利用结构生物学和化学生物学提高 CPT-11 功效
- 批准号:
8817985 - 财政年份:2014
- 资助金额:
$ 26.39万 - 项目类别:
Improving CPT-11 Efficacy Using Structural and Chemical Biology
利用结构生物学和化学生物学提高 CPT-11 功效
- 批准号:
8931901 - 财政年份:2014
- 资助金额:
$ 26.39万 - 项目类别:
Improving CPT-11 Efficacy Using Structural and Chemical Biology
利用结构生物学和化学生物学提高 CPT-11 功效
- 批准号:
9128581 - 财政年份:2014
- 资助金额:
$ 26.39万 - 项目类别:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 26.39万 - 项目类别:
Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 26.39万 - 项目类别:
Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 26.39万 - 项目类别:
Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 26.39万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 26.39万 - 项目类别:
Standard Grant
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 26.39万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 26.39万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 26.39万 - 项目类别:
EU-Funded
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 26.39万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 26.39万 - 项目类别:
Research Grant