Immunodiversity of plant receptor kinase networks for synthetic circuit design

用于合成电路设计的植物受体激酶网络的免疫多样性

基本信息

  • 批准号:
    10709286
  • 负责人:
  • 金额:
    $ 37.93万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-08-01 至 2028-07-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY Immune systems across kingdoms of life recognize pathogen-associated molecules through germline-encoded innate immune receptors. Receptor repertoires in plants have evolved to detect an especially diverse set of ligands due to massive expansion of the receptor kinase gene family with specialized ligand recognition functions. Pairing receptor sequence diversity with specific recognition functions across 100 million RK genes (350,000 plant species * 500 receptors per genome) is a grand challenge in plant molecular biology. It also presents the opportunity to develop a new class of protein-based sensors for biotechnology. The Steinbrenner lab aims to characterize and deploy this vast plant immunodiversity for ligand-induced modulation of engineered signaling pathways. First, we will define the full ligand space that is monitored by plant receptors by focusing on the large subfamily of leucine-rich repeat receptor kinases (termed receptors here) which bind small peptide epitopes to initiate immune signaling. We will combine evolution- and structure-guided approaches to decode the basis of receptor:ligand specificity, including an extensive phylogenomic analysis, peptide variant libraries, and ancestral sequence reconstruction. We hypothesize that transitions in ligand specificity are marked by amino acid substitutions in predicted ligand binding sites among ancestral receptor genes. For “orphan” receptors lacking defined functions, we will conduct a genomic screen using synthetic DNA libraries encoding candidate pathogen epitopes using both plant and yeast models as reporters for receptor activation. We hypothesize that most receptors involved in plant innate immunity will be activated by specific pathogen-derived peptide sequences. Combined, these approaches will provide basic insights into receptor:ligand specificity as well as a toolkit of extracellular sensor domains responsive to specific peptide agonists. Second, we will leverage the unique network architecture of plant immune networks to engineer synthetic signaling pathways that do not interfere with endogenous animal signaling pathways. The plant receptors studied here signal through heterodimerization with a common co-receptor called BAK1. Co-receptor activation culminates in phosphorylation of substrates based on defined phosphocode motifs. We are currently engineering the human inflammation signaling pathway to accept orthogonal input from plant receptors by incorporating plant kinase substrates into specific, phosphoregulated signaling factors. In parallel, we will use plant receptor:co-receptor heterodimerization as a platform to scaffold endogenous human immune signaling domains from Toll-like receptors. We hypothesize that engineered pathways will allow modular tuning by diverse peptide ligands, providing an alternative to current immunoglobulin or GPCR-based synthetic tools. In summary our lab is poised to deploy tools for receptor de-orphanization and signaling pathway engineering to leverage the immense diversity driven by plant-pathogen co-evolution. (30 lines)
项目总结 不同生命王国的免疫系统通过生殖系编码识别病原体相关分子 先天免疫受体。植物中的受体谱系已经进化到检测到一组特别不同的 由于受体激酶基因家族的大规模扩展而产生的特殊配体识别 功能。在1亿个RK基因中配对具有特定识别功能的受体序列多样性 (350,000种植物*每个基因组500个受体)在植物分子生物学中是一个巨大的挑战。它还 介绍了为生物技术开发一类新的蛋白质传感器的机会。施泰因布伦纳 实验室的目标是表征和部署这种巨大的植物免疫多样性,用于配体诱导的调节 设计了信号通路。 首先,我们将通过关注大亚家族来定义由植物受体监控的完整的配基空间 富含亮氨酸的重复受体激酶(这里称为受体),它结合小肽表位启动 免疫信号。我们将结合进化和结构指导的方法来解码 受体:配体特异性,包括广泛的系统基因组分析,多肽变异库,以及 祖先序列重建。我们假设配体专一性的转变是由氨基标记的。 祖先受体基因间预测的配基结合部位的酸取代。对于“孤儿”受体 由于缺乏明确的功能,我们将使用编码候选基因的合成DNA文库进行基因组筛选 使用植物和酵母模型作为受体激活报告的病原体表位。我们假设 大多数参与植物天然免疫的受体将被特定的病原体衍生的多肽激活 序列。结合起来,这些方法将提供对受体的基本见解:配体特异性以及 对特定多肽激动剂作出反应的细胞外感受器结构域工具包。 其次,我们将利用植物免疫网络的独特网络体系结构来设计合成 不干扰内源性动物信号通路的信号通路。植物受体 这里研究的信号是通过与一种共同的共受体BAK1发生异源二聚反应来实现的。共受体激活 根据定义的磷酸代码基序,底物的最终磷酸化。我们目前正在 设计人类炎症信号通路,通过以下方式接受植物受体的正交输入 将植物激酶底物加入到特定的、磷调节的信号因子中。同时,我们将使用 植物受体:共受体异源二聚化作为构建人体内源性免疫信号的平台 Toll样受体的结构域。我们假设,工程路径将允许模块化调整,通过 多样化的多肽配体,为目前的免疫球蛋白或基于GPCR的合成工具提供了一种替代。在……里面 摘要我们的实验室准备部署受体去孤儿和信号通路工程工具来 利用植物-病原体共同进化所驱动的巨大多样性。(30行)

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 }}

Adam D Steinbrenner其他文献

Adam D Steinbrenner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 }}

相似海外基金

Phenotypic consequences of a modern human-specific amino acid substitution in ADSL
ADSL 中现代人类特异性氨基酸取代的表型后果
  • 批准号:
    24K18167
  • 财政年份:
    2024
  • 资助金额:
    $ 37.93万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Estimation of stability and functional changes due to amino acid substitution using molecular simulations
使用分子模拟估计氨基酸取代引起的稳定性和功能变化
  • 批准号:
    20H03230
  • 财政年份:
    2020
  • 资助金额:
    $ 37.93万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Elucidation of the mechanisms of prion protein conversion caused by an amino acid substitution in glycosylphosphatidylinositol anchoring signal peptide
阐明糖基磷脂酰肌醇锚定信号肽中氨基酸取代引起的朊病毒蛋白转化机制
  • 批准号:
    16K18790
  • 财政年份:
    2016
  • 资助金额:
    $ 37.93万
  • 项目类别:
    Grant-in-Aid for Young Scientists (B)
Amino acid substitution without genetic modification
无需基因改造的氨基酸替代
  • 批准号:
    15H05491
  • 财政年份:
    2015
  • 资助金额:
    $ 37.93万
  • 项目类别:
    Grant-in-Aid for Young Scientists (A)
Study on PSII hydrogen bond networks by exhaustive amino acid substitution
穷举氨基酸取代研究PSII氢键网络
  • 批准号:
    15K07110
  • 财政年份:
    2015
  • 资助金额:
    $ 37.93万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Elucidation of the effect of HCV propagationa and IFN sensitivity by amino acid substitution in interferon sensitivity-determining region.
阐明干扰素敏感性决定区氨基酸取代对 HCV 传播和干扰素敏感性的影响。
  • 批准号:
    26860309
  • 财政年份:
    2014
  • 资助金额:
    $ 37.93万
  • 项目类别:
    Grant-in-Aid for Young Scientists (B)
The analysis of the restriction of amino acid substitution on the hemagglutinin molecule of influenza A virus
甲型流感病毒血凝素分子氨基酸取代限制性分析
  • 批准号:
    14370104
  • 财政年份:
    2002
  • 资助金额:
    $ 37.93万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Changes in the Substrate Specificities of Farnesyl Diphosphate Synthase by a Single Amino Acid Substitution
单一氨基酸取代对法尼基二磷酸合酶底物特异性的变化
  • 批准号:
    12680587
  • 财政年份:
    2000
  • 资助金额:
    $ 37.93万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Analyses of the Relationship between Amino Acid Substitution and Phenotype of the Tail Sheath Protein of Bacteriophage T4
噬菌体T4尾鞘蛋白氨基酸取代与表型关系分析
  • 批准号:
    02680125
  • 财政年份:
    1990
  • 资助金额:
    $ 37.93万
  • 项目类别:
    Grant-in-Aid for General Scientific Research (C)
Hypothesis: Both appearance and disappearance of viruses are controlled by the accumulation of amino acid substitution in receptor binding domain
假设:病毒的出现和消失都是由受体结合​​域氨基酸取代的积累控制的
  • 批准号:
    02454184
  • 财政年份:
    1990
  • 资助金额:
    $ 37.93万
  • 项目类别:
    Grant-in-Aid for General Scientific Research (B)
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了