Mechanisms to restrain social cheating from quorum sensing in Pseudomonas aerugin

铜绿假单胞菌群体感应中抑制社会作弊的机制

基本信息

  • 批准号:
    8665380
  • 负责人:
  • 金额:
    $ 17.58万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-06-01 至 2017-05-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): This resubmission for a K08 physician-scientist career award is for support to transition to a career of independent investigation in the field of Pseudomonas aeruginosa quorum sensing. I recently transitioned from fellow to Acting Instructor of Pulmonary and Critical Care Medicine at the University of Washington (UW) and am conducting research in the lab of E. Peter Greenberg in the Department of Microbiology. I have the immediate goal of continuing my research into the evolution of quorum sensing that I initiated as a fellow. The Greenberg lab, Pulmonary Division, and the University of Washington all provide outstanding support to me. Dr. Greenberg is an authority on quorum sensing and bacterial pathogenesis, and I will continue to work in his group and its resources as I transition to an independent research career. The Pulmonary Division and the School of Medicine will ensure that, in addition to the funds provided, I have protected time for research and the institutional support necessary to achieve my long-term goal of independent investigation. This includes a mentoring committee composed of physician-scientists and clinicians, in addition to Dr. Greenberg, to ensure my continued progress during the term of this award. I propose the following research in this application: P. aeruginosa is a leading cause of morbidity and mortality in the genetic disease cystic fibrosis (CF). It also causes difficult-to-treat burn and diabetic wound infections, keratitis, and ventilator-associated pneumonia. P. aeruginosa engages in quorum sensing, a cell-density-dependent intercellular signaling mechanism that coordinates group behaviors including production of virulence factors and secreted proteases. P. aeruginosa quorum sensing is mediated in part by the transcription factor LasR. LasR regulates the transcription of hundreds of genes, many of which encode proteins that are involved in the production of secreted products. Such secreted products are "public goods" that are available to an entire community, not only the producing cell. As such, quorum sensing is susceptible to social cheating, wherein individuals mutate LasR so that they gain benefit from public goods without bearing a metabolic cost of production. In the CF lung, the frequency of LasR mutants can be high and these LasR mutants, which evolve de novo in the lung, have been implicated in the pathogenesis and progression of CF-related lung disease. In the laboratory, P. aeruginosa LasR mutants can evolve from the wildtype under conditions where a quorum-sensing-controlled secreted protease is required for growth. LasR mutants benefit from protease production by the wildtype and these LasR mutants achieve a population equilibrium with the wildtype. In my initial experiments, I showed that the emergence of LasR mutants can be prevented by the availability of adenosine, a "private good" and quorum-sensing controlled nutrient. This provides a mechanism for the population to police against deviant behavior. My proposal seeks to build on these initial experiments by answering the following questions: (1) What are the mechanisms by which the wildtype and LasR mutants achieve an equilibrium with one another? Because quorum sensing requires a sufficient density of cooperators, the emergence of LasR mutants should cause population collapse by reducing the number of cooperators below the threshold, but this does not occur; I seek reasons why. (2) Does spatial structure affect the emergence and frequency of LasR mutants? Infectious settings, including the CF lung, are likely to be structured and I propose to study the effects of spatial structure on the ability of LasR mutants to emerge in a population. Finally, (3), it has been proposed that the CF lung is a singular environment that supports the emergence of LasR mutants. I plan to test this hypothesis by collecting 100 or more environmental samples of P. aeruginosa and examining them for lasR mutations. The experiments described in this proposal will advance our knowledge of the evolution of cooperative behavior and give insight into the ecology of the CF lung.
描述(由申请人提供):此重新提交K08医师科学家职业奖的重新提交是为了过渡到铜绿假单胞菌Quorum Sensing领域的独立调查职业。我最近从华盛顿大学(UW)从肺和重症监护医学的代理讲师过渡到代理讲师,并在微生物学系的E. Peter Greenberg实验室进行了研究。我的直接目标是继续研究我作为家伙发起的Quorum Sensing的演变。格林伯格实验室,肺部和华盛顿大学都为我提供了出色的支持。格林伯格博士是法定人数感测和细菌发病机理的权威,当我过渡到独立研究职业时,我将继续在他的小组及其资源中工作。肺部和医学院将确保除了提供的资金外,我还保护了研究时间以及实现我独立调查的长期目标所必需的机构支持。这包括一个由医师科学家和临床医生组成的指导委员会,除了格林伯格博士之外,还包括我在该奖项期间继续进步。我在此应用中提出以下研究:铜绿假单胞菌是发病率和死亡率的主要原因 在遗传病囊性纤维化(CF)中。它还引起难以治疗的烧伤和糖尿病伤口感染,角膜炎和呼吸机相关的肺炎。铜绿假单胞菌参与群体传感,这是一种依赖细胞密度的细胞间信号传导机制,可协调组行为,包括产生毒力因子和分泌的蛋白酶。铜绿假单胞菌群体传感部分由转录因子LASR介导。 LASR调节了数百个基因的转录,其中许多基因编码与分泌产物生产有关的蛋白质。这种分泌的产品是整个社区可用的“公共物品”,而不仅仅是生产单元。因此,法定人心的感知容易受到社会作弊的影响,其中个人会突变LASR,因此他们从公共物品中受益而无需代谢生产成本。在CF肺中,LASR突变体的频率可以很高,而这些在肺中从头进化的LASR突变体已与CF相关肺部疾病的发病机理和进展有关。在实验室中,铜绿假单胞菌LASR突变体可以从野生型中演变,而野生型则需要群体感应控制的分泌蛋白酶才能生长。 LASR突变体受益于野生型蛋白酶的产生,而这些LASR突变体可以与野生型实现种群平衡。在我的最初实验中,我表明可以通过腺苷的可用性来防止LASR突变体的出现,腺苷的可用性是一种“私人商品”和群体感应的受控营养素。这为人口提供了一种机制,使人反对偏差行为。我的提议试图通过回答以下问题来建立这些最初的实验:(1)野生型和LASR突变体相互达到平衡的机制是什么?由于法定人数的传感需要足够的合作者密度,因此LASR突变体的出现应通过减少阈值以下的合作者数量来导致种群崩溃,但这不会发生。我寻求原因。 (2)空间结构是否会影响LASR突变体的出现和频率?包括CF肺在内的传染性环境可能是结构化的,我建议研究空间结构对 LASR突变体在人群中出现的能力。最后(3),有人提出CF肺是一个支持LASR突变体出现的单数环境。我计划通过收集铜绿假单胞菌的100个或更多环境样本来检验这一假设,并检查它们是否有LASR突变。该提案中描述的实验将提高我们对合作行为演变的了解 并深入了解CF肺的生态。

项目成果

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Ajai Dandekar其他文献

Ajai Dandekar的其他文献

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{{ truncateString('Ajai Dandekar', 18)}}的其他基金

Quinolone and acyl-homoserine lactone quorum sensing in chronic P. aeruginosa infections
慢性铜绿假单胞菌感染中的喹诺酮和酰基高丝氨酸内酯群体感应
  • 批准号:
    10711652
  • 财政年份:
    2023
  • 资助金额:
    $ 17.58万
  • 项目类别:
Pseudomonas aeruginosa quorum sensing
铜绿假单胞菌群体感应
  • 批准号:
    10080743
  • 财政年份:
    2018
  • 资助金额:
    $ 17.58万
  • 项目类别:
Pseudomonas aeruginosa quorum sensing
铜绿假单胞菌群体感应
  • 批准号:
    10319599
  • 财政年份:
    2018
  • 资助金额:
    $ 17.58万
  • 项目类别:
Mechanisms to restrain social cheating from quorum sensing in Pseudomonas aerugin
铜绿假单胞菌群体感应中抑制社会作弊的机制
  • 批准号:
    8581055
  • 财政年份:
    2013
  • 资助金额:
    $ 17.58万
  • 项目类别:
Mechanisms to restrain social cheating from quorum sensing in Pseudomonas aerugin
铜绿假单胞菌群体感应中抑制社会作弊的机制
  • 批准号:
    8852532
  • 财政年份:
    2013
  • 资助金额:
    $ 17.58万
  • 项目类别:
Pathogenesis of MHV-induced demyelination
MHV 诱导的脱髓鞘的发病机制
  • 批准号:
    6779113
  • 财政年份:
    2001
  • 资助金额:
    $ 17.58万
  • 项目类别:
Pathogenesis of MHV-induced demyelination
MHV 诱导的脱髓鞘的发病机制
  • 批准号:
    6830192
  • 财政年份:
    2001
  • 资助金额:
    $ 17.58万
  • 项目类别:

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