Supplement to Advancing CRISPR-Cas Technologies for the Discovery and Characterization of Novel Fungal Natural Products
先进 CRISPR-Cas 技术的补充,用于新型真菌天然产物的发现和表征
基本信息
- 批准号:10805704
- 负责人:
- 金额:$ 1.09万
- 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:2020-08-01 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:AcademiaAnabolismBioinformaticsCRISPR/Cas technologyCharacteristicsChemical StructureChemicalsClustered Regularly Interspaced Short Palindromic RepeatsComplexDedicationsDevelopmentDrug IndustryDrug resistanceEnzymesFungal GenomeFungal PeptidesGene ClusterGenesGeneticGenome engineeringGoalsHumanInvestigationMedicineMoldsNatural ProductsParentsPathway interactionsPeptidesPharmacologic SubstancePlayPropertyResearchRibosomesRoleSourceTechnologyTextTherapeuticalgorithm developmentanalogbioinformatics tooldrug candidatedrug discoveryfungusgenetic manipulationgenome editinghuman diseaseinterestnext generationnovelnovel therapeuticspeptide natural productspharmacologictool
项目摘要
Project Summary/Abstract (30 lines of text)
Fungal natural products (NPs) have been a preeminent source of medicine and played pivotal
roles as pharmaceuticals for the treatment of human diseases. The rapid expansion of fungal
genome sequences and the development of bioinformatics tools have enabled the identification
of thousands of fungal NP biosynthetic gene clusters (BGCs), thus providing an unprecedented
opportunity to discover new fungal NPs. However, the discovery of new bioactive fungal NPs
remains challenging, due to difficulties in prioritizing BGCs and genetic manipulations in fungi. In
this proposal, we expect to build pipelines to rapidly discover novel bioactive fungal natural
products that can serve as the next generation of drug candidates for the treatment of human
diseases; to do this, we will apply the CRISPR Cas genome editing technologies and dedicate
these tools to the biosynthesis of fungal natural products. To achieve the research goal, our first
direction will focus on identifying and characterizing rarely discovered ribosomally synthesized
and post-translationally modified peptides (RiPPs) from fungal origins. Due to RiPPs’ unique
biosynthetic machinery, complex chemical characteristics, and important pharmacological
properties, bacterial RiPPs have drawn strong interest from both academia and the
pharmaceutical industry. However, only a handful of RiPPs have been identified from fungi, even
though fungi is known to be a prolific producer of NPs. By characterizing novel biosynthetic
enzymes of known RiPPs and new fungal BGCs identified by bioinformatics analysis, we expect
to greatly broaden and deepen our understanding of the biosynthesis of fungal RiPPs and expand
the repertoire of novel fungal RiPP NPs. Our second direction will focus on expanding and
applying CRISPR-based genome engineering toolkits to characterize biosynthetic gene clusters
from filamentous fungi. CRISPR-Cas tools have been successfully demonstrated to be feasible
in fungal species but are rarely applied in the investigation of fungal NP biosynthesis. We will
develop complementary sets of CRISPR-Cas tools for manipulating fungal biosynthetic gene
clusters in both native and heterologous expression hosts. By doing so, we expect to develop a
full set of CRISPR gene-editing toolkits to rapidly carry out genetic manipulations to study natural
product biosynthesis in filamentous fungi. Together, the two research directions and collaborative
research endeavors through BGC characterization, genetic tool advancement, and new
bioinformatics algorithm development will build a complete pipeline to significantly increase the
repertoire of fungal NPs and analogs, especially fungal RiPPs, making these molecules valuable
drug candidates for human therapeutics.
项目摘要/摘要(30行文本)
真菌天然产物(NPs)是一种重要的药物来源,
作为治疗人类疾病的药物的作用。真菌的迅速扩张
基因组序列和生物信息学工具的发展使识别
数以千计的真菌NP生物合成基因簇(BGC),从而提供了前所未有的
有机会发现新的真菌纳米粒子。然而,新的生物活性真菌纳米颗粒的发现,
由于在优先考虑BGC和真菌中的遗传操作方面存在困难,因此仍然具有挑战性。在
这一建议,我们希望建立管道,以快速发现新的生物活性真菌天然
产品,可以作为下一代候选药物治疗人类
为此,我们将应用CRISPR Cas基因组编辑技术,
这些工具的生物合成真菌天然产物。为了实现研究目标,我们首先
方向将集中在识别和表征罕见的核糖体合成
和来自真菌来源的后修饰肽(RIPPs)。由于RIP的独特性,
生物合成机制,复杂的化学特性,以及重要的药理作用,
细菌RIPP的特性引起了学术界和
医药行业。然而,只有少数RIPP已被确定从真菌,甚至
尽管已知真菌是NP的多产者。通过表征新的生物合成
通过生物信息学分析确定了已知的RIPPs和新的真菌BGC的酶,我们预计
大大拓宽和加深我们对真菌RIPPs生物合成的理解,
新的真菌RiPP NP的库。我们的第二个方向将专注于扩大和
应用基于CRISPR的基因组工程工具包来表征生物合成基因簇
从丝状真菌。CRISPR-Cas工具已被成功证明是可行的
但很少应用于真菌NP生物合成的研究。我们将
开发用于操纵真菌生物合成基因的互补CRISPR-Cas工具集
在天然和异源表达宿主中的簇。通过这样做,我们希望开发一个
全套CRISPR基因编辑工具包,可快速进行基因操作,
丝状真菌中的产物生物合成。这两个研究方向和合作
通过BGC表征,遗传工具的进步,以及新的
生物信息学算法开发将建立一个完整的管道,以显着增加
真菌NP和类似物,特别是真菌RIPPs的库,使这些分子有价值
用于人类治疗的候选药物。
项目成果
期刊论文数量(9)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Structural basis of the stereoselective formation of the spirooxindole ring in the biosynthesis of citrinadins.
- DOI:10.1038/s41467-021-24421-0
- 发表时间:2021-07-06
- 期刊:
- 影响因子:16.6
- 作者:Liu Z;Zhao F;Zhao B;Yang J;Ferrara J;Sankaran B;Venkataram Prasad BV;Kundu BB;Phillips GN Jr;Gao Y;Hu L;Zhu T;Gao X
- 通讯作者:Gao X
Advances in genome editing for genetic hearing loss.
- DOI:10.1016/j.addr.2020.05.001
- 发表时间:2021-01
- 期刊:
- 影响因子:16.1
- 作者:Ding N;Lee S;Lieber-Kotz M;Yang J;Gao X
- 通讯作者:Gao X
Quinolactacin Biosynthesis Involves Non-Ribosomal-Peptide-Synthetase-Catalyzed Dieckmann Condensation to Form the Quinolone-γ-lactam Hybrid.
- DOI:10.1002/anie.202005770
- 发表时间:2020-10-19
- 期刊:
- 影响因子:16.6
- 作者:Zhao, Fanglong;Liu, Zhiwen;Yang, Shuyuan;Ding, Ning;Gao, Xue
- 通讯作者:Gao, Xue
Utilizing a cell-free protein synthesis platform for the biosynthesis of a natural product, caffeine.
- DOI:10.1093/synbio/ysad017
- 发表时间:2023
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
Unraveling the biosynthesis of penicillenols by genome mining PKS-NRPS gene clusters in Penicillium citrinum.
通过基因组挖掘柑橘青霉中的 PKS-NRPS 基因簇来揭示青霉烯醇的生物合成。
- DOI:10.1002/aic.17885
- 发表时间:2022
- 期刊:
- 影响因子:0
- 作者:Nie,Qiuyue;Guo,Shuqi;Gao,Xue
- 通讯作者:Gao,Xue
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{{ truncateString('Xue Gao', 18)}}的其他基金
Develop High-Precision and Multiplex Base Editing Approaches for Therapeutic Applications
开发用于治疗应用的高精度和多重碱基编辑方法
- 批准号:
10591575 - 财政年份:2021
- 资助金额:
$ 1.09万 - 项目类别:
Develop High-Precision and Multiplex Base Editing Approaches for Therapeutic Applications
开发用于治疗应用的高精度和多重碱基编辑方法
- 批准号:
10185829 - 财政年份:2021
- 资助金额:
$ 1.09万 - 项目类别:
Develop High-Precision and Multiplex Base Editing Approaches for Therapeutic Applications
开发用于治疗应用的高精度和多重碱基编辑方法
- 批准号:
10383725 - 财政年份:2021
- 资助金额:
$ 1.09万 - 项目类别:
Advancing CRISPR-Cas Technologies for the Discovery and Characterization of Novel Fungal Natural Products
推进 CRISPR-Cas 技术用于新型真菌天然产物的发现和表征
- 批准号:
10029379 - 财政年份:2020
- 资助金额:
$ 1.09万 - 项目类别:
Advancing CRISPR-Cas Technologies for the Discovery and Characterization of Novel Fungal Natural Products
推进 CRISPR-Cas 技术用于新型真菌天然产物的发现和表征
- 批准号:
10624347 - 财政年份:2020
- 资助金额:
$ 1.09万 - 项目类别:
Advancing CRISPR-Cas Technologies for the Discovery and Characterization of Novel Fungal Natural Products
推进 CRISPR-Cas 技术用于新型真菌天然产物的发现和表征
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10223384 - 财政年份:2020
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Undergraduate Jeffrey Vanegas Research Experience for underrepresented biomedical research students
本科杰弗里·瓦内加斯(Jeffrey Vanegas)为代表性不足的生物医学研究生提供的研究经验
- 批准号:
10408899 - 财政年份:2020
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$ 1.09万 - 项目类别:
Supplement to Advancing CRISPR-Cas Technologies for Discovery and Characterization of Novel Fungal Natural Products
先进 CRISPR-Cas 技术的补充,用于新型真菌天然产物的发现和表征
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$ 1.09万 - 项目类别:
Advancing CRISPR-Cas Technologies for the Discovery and Characterization of Novel Fungal Natural Products
推进 CRISPR-Cas 技术用于新型真菌天然产物的发现和表征
- 批准号:
10397411 - 财政年份:2020
- 资助金额:
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