Gut bacterial metabolism of the side-chain of corticosteroids
皮质类固醇侧链的肠道细菌代谢
基本信息
- 批准号:10703384
- 负责人:
- 金额:$ 36.08万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-15 至 2026-07-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAdrenal Cortex HormonesAffectAmino Acid SequenceAnaerobic BacteriaAndrogensAndrostenedioneAnimal ModelBacteriaBase SequenceBiochemicalBioinformaticsBiological AssayCollectionColon CarcinomaCommunitiesCytochrome P450DataDiseaseEnzyme Inhibitor DrugsEnzymesEscherichia coliFecesFundingFutureGene ClusterGenesGlucocorticoidsGoalsHealthHealth PromotionHomologous GeneHumanHuman MicrobiomeHydrocortisoneHypertensionIntestinesKetonesKetosteroidsKnowledgeLibrariesMalignant neoplasm of prostateMapsMetabolic BiotransformationMetabolismMetagenomicsMethodologyMissionMixed Function OxygenasesOrganismOxidoreductaseOxygenPathway interactionsPeripheralPhylogenetic AnalysisPhysiologyProbioticsProcessProgesteroneReactionResearchRisk FactorsSideSteroidsTestosteroneTherapeuticTissuesTransketolaseUnited States National Institutes of HealthUrinary tractbacterial metabolismbile acid metabolismbiobankdehydroxylationgene discoverygut bacteriagut microbiomehost-associated microbial communitieshost-microbe interactionshydroxyl grouphypertensiveimmune functioninnovationmetabolomemetabolomicsmetagenomemicrobialmicrobiomenovelpreventprotein expressionprotein foldingscreeningsteroid metabolismstool samplesynthetic biologytherapeutic targettranscriptome sequencingtranscriptomicstranslational approach
项目摘要
Project Summary
The metabolism of corticosteroids by host-associated microbiomes rivals that of host peripheral tissues. Side-
chain metabolism of corticosteroids is capable of changing the functional class of steroid. The focus of the current
project is elucidating the microbial enzymes involved in (Aim 1) the side-chain cleavage of cortisol and reduction
of 17-keto resulting in 11-oxy-androgens (Aim 2) 21-dehydroxylation yielding 11-oxy-progesterone derivatives.
These pathways are significant because they are hypothesized to potentiate diseases relevant to the mission of
NIH. The formation of 11-oxy-androgens in the intestine and urinary tract is hypothesized to affect host immune
function, and may be a risk factor for prostate cancer. The formation of 11-oxy-progesterone derivatives has
been shown to be pro-hypertensive through a well-established mechanism involving the ‘dehydrogenase
hypothesis’. Our preliminary data demonstrates that we have established the side-chain cleavage enzyme,
steroid-17,20-desmolase, from both gut and urinary tract bacteria. The end-product 17-keto steroid can then be
reduced to either testosterone or epitestosterone derivatives. We have cultured anaerobes that encode the
enzymes for (epi)testosterone formation, and our preliminary data demonstrates our expertise and the feasibility
of locating and characterizing these enzymes. We also show a cultured anaerobe capable of corticosteroid 21-
dehydroxylation and formulated a hypothesis and preliminary data that a putative corticosteroid dehydroxylation
(csd) gene cluster encodes 21-dehydroxylation. Once located, we will apply previously established bioinformatics
approaches to uncover the diversity of host-associated bacteria encoding homologous sterolbiome enzymes
(phylogenetic analysis, sequence similarity networks). However, to address evolutionarily analogous sterolbiome
enzymes with the same functions described above, we will utilize an unbiased functional metagenomic approach.
We present additional robust preliminary data demonstrating the feasibility of our studies that include (1)
collection of 180 stool samples for functional metagenomic screening (2) utilization of RNA-Seq for steroid-
inducible gene discovery (3) heterologous expression and characterization of numerous microbial sterolbiome
enzymes (3) establishment of enzyme assays and steroid metabolomics. The research proposed in this
application is innovative, in our opinion, because it represents a new and substantive departure from the status
quo established four decades ago by combining transcriptomics, heterologous protein expression, enzyme
assays, phylogenetic and sequence similarity networks, synthetic biology, and functional metagenomic
screening to discover the precise nucleic acid sequences encoding corticosteroid side-chain metabolizing
enzymes. Successful completion will potentiate research into the cause and effect relationships between the gut
sterolbiome and host diseases, and is expected to lead to translational approaches (probiotics, enzyme
inhibitors) to modulate the gut microbiome to restore and maintain health.
项目概要
宿主相关微生物组对皮质类固醇的代谢与宿主外周组织的代谢相当。边-
皮质类固醇的链代谢能够改变类固醇的功能类别。当前的重点
该项目正在阐明参与(目标 1)皮质醇侧链裂解和还原的微生物酶
17-酮基产生11-氧雄激素(目标2)21-脱羟基产生11-氧孕酮衍生物。
这些途径很重要,因为它们被假设会增强与人类使命相关的疾病。
NIH。推测肠道和泌尿道中 11-氧雄激素的形成会影响宿主免疫
功能,并且可能是前列腺癌的危险因素。 11-氧孕酮衍生物的形成
已被证明通过涉及“脱氢酶”的完善机制具有促高血压作用
假设'。我们的初步数据表明我们已经建立了侧链裂解酶,
类固醇-17,20-去氨酶,来自肠道和尿路细菌。最终产品 17-酮类固醇可以
还原为睾酮或表睾酮衍生物。我们培养了编码厌氧菌
用于(表)睾酮形成的酶,我们的初步数据证明了我们的专业知识和可行性
定位和表征这些酶。我们还展示了一种能够产生皮质类固醇 21- 的培养厌氧菌
脱羟基并提出了假设和初步数据,假定皮质类固醇脱羟基
(csd) 基因簇编码 21-脱羟基。一旦找到,我们将应用先前建立的生物信息学
揭示编码同源甾醇生物组酶的宿主相关细菌多样性的方法
(系统发育分析、序列相似性网络)。然而,为了解决进化上类似的甾醇生物组
具有上述相同功能的酶,我们将利用无偏见的功能宏基因组方法。
我们提供了额外可靠的初步数据,证明我们研究的可行性,包括(1)
收集 180 份粪便样本进行功能宏基因组筛选 (2) 利用 RNA-Seq 进行类固醇-
诱导基因的发现(3)众多微生物甾醇生物组的异源表达和表征
(3)酶测定法和类固醇代谢组学的建立。本文提出的研究
我们认为,该应用程序是创新的,因为它代表了与现状的新的实质性背离
四十年前通过结合转录组学、异源蛋白质表达、酶而建立的现状
分析、系统发育和序列相似性网络、合成生物学和功能宏基因组
筛选以发现编码皮质类固醇侧链代谢的精确核酸序列
酶。成功完成将加强对肠道之间因果关系的研究
固醇生物组和宿主疾病,并有望导致转化方法(益生菌、酶
抑制剂)来调节肠道微生物组以恢复和维持健康。
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 }}
Jason Michael Ridlon其他文献
Jason Michael Ridlon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('Jason Michael Ridlon', 18)}}的其他基金
Role of Gut Bacterial Side-Chain Cleavage of Cortisol in Host 11Beta-Hydroxyandrostenedione Formation
肠道细菌皮质醇侧链裂解在宿主 11β-羟基雄烯二酮形成中的作用
- 批准号:
10726864 - 财政年份:2020
- 资助金额:
$ 36.08万 - 项目类别:
Role of Gut Bacterial Side-Chain Cleavage of Cortisol in Host 11Beta-Hydroxyandrostenedione Formation
肠道细菌皮质醇侧链裂解在宿主 11β-羟基雄烯二酮形成中的作用
- 批准号:
10594989 - 财政年份:2020
- 资助金额:
$ 36.08万 - 项目类别:
Studies towards a pan-genome and genetic manipulation of Clostridium scindens
梭菌的全基因组和遗传操作研究
- 批准号:
10113519 - 财政年份:2020
- 资助金额:
$ 36.08万 - 项目类别:
Role of Gut Bacterial Side-Chain Cleavage of Cortisol in Host 11Beta-Hydroxyandrostenedione Formation
肠道细菌皮质醇侧链裂解在宿主 11β-羟基雄烯二酮形成中的作用
- 批准号:
10370361 - 财政年份:2020
- 资助金额:
$ 36.08万 - 项目类别:
Studies towards a pan-genome and genetic manipulation of Clostridium scindens
梭菌的全基因组和遗传操作研究
- 批准号:
9979542 - 财政年份:2020
- 资助金额:
$ 36.08万 - 项目类别:
Characterization of bacterial reductases acting on the A-ring of 11-oxy-androgens
作用于 11-氧雄激素 A 环的细菌还原酶的表征
- 批准号:
10653436 - 财政年份:2020
- 资助金额:
$ 36.08万 - 项目类别:














{{item.name}}会员




