Tunable therapeutic modulation of the gut microbiome by engineered probiotics

通过工程益生菌对肠道微生物组进行可调节的治疗调节

基本信息

  • 批准号:
    10451749
  • 负责人:
  • 金额:
    $ 68.33万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-08-10 至 2024-07-31
  • 项目状态:
    已结题

项目摘要

ABSTRACT Engineered probiotics represent a powerful tool with which to ‘knock-in’ gene functions and pathways into the gut microbiome, alter the structure of the gut microbiome to test hypotheses regarding community architecture and disease, and to deliver therapeutics. However, known probiotics fail to persist in the gut due to colonization resistance by the gut microbiota, limiting their value as either research or therapeutic tools. Further, controlled delivery of therapeutics and other gene products by engineered probiotics is limited by a lack of robust and tunable synthetic biology tools for the complex in vivo environment. The rationale for the proposed research is that the promise of probiotic therapies is currently limited by poor persistence and a lack of robust engineering tools. The central motivation for this proposal is to understand the host and microbial mechanisms governing probiotic integration and develop tools to engineer probiotic therapies. Guided by strong preliminary data, this interdisciplinary proposal will pursue three specific aims: to 1) identify determinants of probiotic colonization in the gut, 2) design and optimize gut-relevant biosensor and expression circuits, and 3) demonstrate the efficacy of in vivo delivery of a phenylketonuria (PKU) therapeutic by an enhanced probiotic colonizer. The first aim of this proposal is to optimize and identify mechanisms of probiotic colonization, testing the hypothesis that probiotic gut colonization is enhanced and tunable by modulating expression of colonization factors selected from fecal metagenomes. In particular, we will select for durable colonizers from probiotics expressing an exhaustive combinatorial library of colonization factors driven by in vivo characterized promoters. The second aim is to develop synthetic biology tools for tunable gene expression control and biocontainment of engineered probiotics, testing the hypothesis that combining sensors for temperature, pH, bile acids, and short chain fatty acids will enable spatial control over gene expression along the gastrointestinal tract. The third aim is to demonstrate that the engineered probiotic chassis can reliably deliver therapeutics to the gut, testing the hypothesis that our engineered probiotic can stably deliver phenylalanine-ammonia lyase (Pal2) in a murine model of PKU to decrease serum phenylalanine. This proposal is innovative because our integrated and complementary research team will improve understanding of probiotic therapies at both basic science and translational levels. The proposed experiments are significant in that they will 1) improve our understanding of the genetic elements and microbial interactions governing gastrointestinal colonization, 2) generate and optimize synthetic biology tools for in vivo circuit control that will be modular and widely applicable to probiotic engineering, and 3) explore the efficacy of an alternative, continual-delivery therapeutic for PKU. The proposed research is impactful because it will 1) develop reliable probiotic colonizers, 2) update the toolbox for synthetic biology in vivo applications, and 3) establish engineered probiotics as vehicles for sustained therapeutic delivery or controlled modulation of gut community architectures.
摘要

项目成果

期刊论文数量(10)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Engineering ligand-specific biosensors for aromatic amino acids and neurochemicals.
  • DOI:
    10.1016/j.cels.2021.10.006
  • 发表时间:
    2022-03-16
  • 期刊:
  • 影响因子:
    9.3
  • 作者:
    Rottinghaus AG;Xi C;Amrofell MB;Yi H;Moon TS
  • 通讯作者:
    Moon TS
Engineering microbial diagnostics and therapeutics with smart control.
具有智能控制的工程微生物诊断和治疗学。
  • DOI:
    10.1016/j.copbio.2020.05.006
  • 发表时间:
    2020-12
  • 期刊:
  • 影响因子:
    7.7
  • 作者:
    Amrofell MB;Rottinghaus AG;Moon TS
  • 通讯作者:
    Moon TS
Genetically stable CRISPR-based kill switches for engineered microbes.
  • DOI:
    10.1038/s41467-022-28163-5
  • 发表时间:
    2022-02-03
  • 期刊:
  • 影响因子:
    16.6
  • 作者:
    Rottinghaus AG;Ferreiro A;Fishbein SRS;Dantas G;Moon TS
  • 通讯作者:
    Moon TS
Engineering E. coli strains using antibiotic-resistance-gene-free plasmids.
  • DOI:
    10.1016/j.crmeth.2023.100669
  • 发表时间:
    2023-12-18
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Amrofell, Matthew B.;Rengarajan, Sunaina;Vo, Steven T.;Tovar, Erick S. Ramirez;Lobello, Larissa;Dantas, Gautam;Moon, Tae Seok
  • 通讯作者:
    Moon, Tae Seok
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Gautam Dantas其他文献

Gautam Dantas的其他文献

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{{ truncateString('Gautam Dantas', 18)}}的其他基金

Impact of early-life perturbations on pediatric microbiome maturation
早期生活扰动对儿科微生物组成熟的影响
  • 批准号:
    10424578
  • 财政年份:
    2021
  • 资助金额:
    $ 68.33万
  • 项目类别:
Impact of early-life perturbations on pediatric microbiome maturation
早期生活扰动对儿科微生物组成熟的影响
  • 批准号:
    10298201
  • 财政年份:
    2021
  • 资助金额:
    $ 68.33万
  • 项目类别:
Impact of early-life perturbations on pediatric microbiome maturation
早期生活扰动对儿科微生物组成熟的影响
  • 批准号:
    10634654
  • 财政年份:
    2021
  • 资助金额:
    $ 68.33万
  • 项目类别:
Occupational Exposure and Health Risk from Dairy Microbiome and Resistome to Dairy Farm Workers
乳制品微生物组和 Resistome 对奶牛场工人的职业暴露和健康风险
  • 批准号:
    10165408
  • 财政年份:
    2018
  • 资助金额:
    $ 68.33万
  • 项目类别:
Tunable therapeutic modulation of the gut microbiome by engineered probiotics
通过工程益生菌对肠道微生物组进行可调节的治疗调节
  • 批准号:
    10207474
  • 财政年份:
    2018
  • 资助金额:
    $ 68.33万
  • 项目类别:
Tunable therapeutic modulation of the gut microbiome by engineered probiotics
通过工程益生菌对肠道微生物组进行可调节的治疗调节
  • 批准号:
    9761466
  • 财政年份:
    2018
  • 资助金额:
    $ 68.33万
  • 项目类别:
Tunable therapeutic modulation of the gut microbiome by engineered probiotics
通过工程益生菌对肠道微生物组进行可调节的治疗调节
  • 批准号:
    9977923
  • 财政年份:
    2018
  • 资助金额:
    $ 68.33万
  • 项目类别:
PHYLOGENOMIC, TRANSCRIPTOMIC, VIROMIC, AND IMMUNOPROTEOMIC DETERMINANTS OF NECROTIZING ENTEROCOLITIS
坏死性小肠结肠炎的系统基因组、转录组、病毒组和免疫蛋白质组决定因素
  • 批准号:
    9559708
  • 财政年份:
    2017
  • 资助金额:
    $ 68.33万
  • 项目类别:
PHYLOGENOMIC, TRANSCRIPTOMIC, VIROMIC, AND IMMUNOPROTEOMIC DETERMINANTS OF NECROTIZING ENTEROCOLITIS
坏死性小肠结肠炎的系统基因组、转录组、病毒组和免疫蛋白质组决定因素
  • 批准号:
    10164835
  • 财政年份:
    2017
  • 资助金额:
    $ 68.33万
  • 项目类别:
PHYLOGENOMIC, TRANSCRIPTOMIC, VIROMIC, AND IMMUNOPROTEOMIC DETERMINANTS OF NECROTIZING ENTEROCOLITIS
坏死性小肠结肠炎的系统基因组、转录组、病毒组和免疫蛋白质组决定因素
  • 批准号:
    9369551
  • 财政年份:
    2017
  • 资助金额:
    $ 68.33万
  • 项目类别:

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