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
• 负责人: Ajai Dandekar
• 金额: $ 17.58万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8852532
• 关键词: Acute; Adenosine; Affect; Agar; Award; Bacteria; Behavior; Binding; Burn injury; Carbon; Caseins; Catabolism; Cause of Death; Cell Density; Cells; Chronic; Communities; Cooperative Behavior; Critical Care; Cystic Fibrosis; Diabetic wound; Disease; Ecology; Elements; Energy-Generating Resources; Ensure; Environment; Equilibrium; Evolution; Eye; Frequencies; Funding; Gene Expression; Genes; Genetic Transcription; Goals; Growth; Hereditary Disease; Human; Individual; Infection; Investigation; Keratitis; Knowledge; Laboratories; Life; Liquid substance; Lung; Lung diseases; Maintenance; Mediating; Medicine; Mentors; Metabolic; Metabolism; Microbiology; Morbidity - disease rate; Mutate; Mutation; Nutrient; Pathogenesis; Patients; Peptide Hydrolases; Physicians; Police; Population; Process; Production; Proteins; Pseudomonas; Pseudomonas aeruginosa; Regulation; Relative (related person); Research; Resources; Sampling; Scientist; Signal Transduction; Structure; System; Testing; Therapeutic Intervention; Time; Universities; Variant; Virulence Factors; Washington; Work; Wound Infection; authority; career; cost; cystic fibrosis patients; density; deviant; insight; instructor; interest; medical schools; mortality; mutant; pathogen; pressure; prevent; public health relevance; quorum sensing; research study; signal processing; social; theories; transcription factor; ventilator-associated pneumonia

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）：本次重新提交的K08医师-科学家职业奖是为了支持过渡到铜绿假单胞菌群体感应领域的独立调查职业。我最近从华盛顿大学（UW）的肺病和危重症医学的研究员转变为代理讲师，并在微生物学系的E. Peter Greenberg的实验室进行研究。我的直接目标是继续我的研究，研究群体感应的进化，这是我作为一名研究员发起的。格林伯格实验室、肺科和华盛顿大学都为我提供了出色的支持。格林伯格博士是群体感应和细菌发病机制方面的权威，我将继续在他的团队及其资源中工作，因为我将过渡到独立的研究生涯。肺科和医学院将确保，除了提供资金外，我有足够的时间进行研究，并为我实现独立研究的长期目标提供必要的机构支持。这包括一个由内科科学家和临床医生组成的指导委员会，除了格林伯格博士，以确保我在这个奖项的期限内继续取得进展。我建议在此应用中进行以下研究：铜绿假单胞菌是发病率和死亡率的主要原因