Shared Host Genetics and Bacterial Adaptation in the Transmission of H. pylori

幽门螺杆菌传播中的共享宿主遗传学和细菌适应

• 批准号: 8437189
• 负责人: Sarah Talarico
• 金额: $ 10.01万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-05 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8437189
• 关键词: Adult; Affect; Bacteria; Bacterial Infections; Base Sequence; Biological; Biological Markers; Cell surface; Cells; Child; Childhood; Cities; Clinical; Collection; Committee Members; DNA; DNA Sequence; Data; Development; Development Plans; Disease Outcome; Epidemiologic Studies; Epidemiologist; Epidemiology; Faculty; Family; Family Relationship; Family member; Feces; Fostering; Fred Hutchinson Cancer Research Center; Future; Gastritis; Genes; Genetic; Genetic Variation; Genotype; Goals; Grant; Helicobacter Infections; Helicobacter pylori; Host Defense; Household; Human; Individual; Infection; Institution; Interdisciplinary Study; Investigation; Knowledge; Literature; Mentors; Methods; Molecular; Molecular Biology; Mutation; Parents; Participant; Pathogenesis; Pattern; Peptic Ulcer; Prevalence; Proteins; Research; Research Design; Research Personnel; Research Proposals; Role; Sampling; Siblings; Specimen; Structure; Supervision; Testing; Training; Ulcer; Universities; Washington; Work; adopted child; arm; bacterial genetics; career; career development; design; epidemiology study; experience; improved; malignant stomach neoplasm; meetings; member; pathogen; post-doctoral training; prevent; programs; research and development; research study; study characteristics; transmission process

DESCRIPTION (provided by applicant): It is my goal to become an independent investigator studying the epidemiology of bacterial infections and the role of bacterial genetic diversity in transmission, pathogenesis, and disease outcome. I envision that my research program will have three interconnected arms: epidemiologic studies involving collection of bacterial samples, investigation of genetic diversity of the bacterial samples and its association with clinical and epidemiological characteristics, and study of the functional impact of the observed genetic diversity. I have gained experience in conducting studies of bacterial genetic diversity and its clinical, epidemiological, and functional relevance through my doctoral work and my post-doctoral training so far. However, I have not yet had any experience in conducting epidemiologic studies that involve collecting bacterial samples and participant data and consider this a major gap in my training and ability to attain my career goals. To fill this gap in my training, I have crafted a research proposal that will allow me to obtain important experience in the design of an epidemiologic study, recruitment of study participants, and collection of biological specimens and subject data under the supervision and guidance of mentors who have extensive experience in conducting these types of studies. The career development plan takes advantage of the variety of expertise among faculty members at The Fred Hutchinson Cancer Research Center (FHCRC), an institution that fosters interdisciplinary research. The proposed research, which integrates epidemiology and molecular biology, will be supervised by a mentoring committee that includes a molecular and cell biologist and H. pylori expert (Dr. Nina Salama, mentor), two epidemiologists (Dr. Johanna Lampe, co-mentor, and Dr. Thomas Vaughan), and a biostatistician (Dr. Sarah Holte). I will meet with my mentor weekly and with my co-mentor at least twice monthly to discuss details of the research study. Twice yearly, I will meet with my entire mentoring committee to present my research progress and discuss future steps for my research and career development. In addition to support from my mentoring committee members, I will take advantage of both the scientific and career development seminars held at FHCRC and the University of Washington. The proposed research is a study of H. pylori transmission within families and the bacterial genetic changes that occur during adaptation to a new host. H. pylori transmission predominantly occurs within families, but it is not known if this is attributable to the sustained close contacts between family members or because the genetic relatedness of the family members facilitates transmission. Bacterial adaptations to the individual host that occur during H. pylori's decades-long infection may cause the strain to be better able to colonize a genetically similar host. H. pylori has many mechanisms for genetic diversification, which likely aids the bacterium in adapting to the newly infected host after transmission. Diversification of genes that encode H. pylori cell surface structures that interact with the host is especially likely to be important during adaptation to a new host. In this grant, test the hypothesis that H. pylori transmission predominantly occurs within families because an H. pylori strain that is adapted to the individual host is better able to colonize a genetically similar host. Furthermore, I test the hypothesis that H. pylori will undergo more genetic diversification when being transmitted between unrelated individuals than between related individuals. Aim 1 proposes to collect stool samples from members of families with biological children and families with adopted children, genotype H. pylori from the stool DNA, and compare the extent of H. pylori genotype sharing, which indicates transmission, between the two different types of families using statistical analysis. In Aim 2, H. pylori DNA isolated from family members who share the same H. pylori strain will be compared by PCR and DNA sequencing to look for genetic changes to genes involved in bacterial-host interactions that would affect expression or function of the encoded protein. The extent of genetic changes within H. pylori strain pairs shared by related and unrelated family members will then be examined. The proposed research will result in important information about the patterns of H. pylori transmission within families and the contribution of shared host genetics versus household contact to transmission. Further knowledge of the factors involved in H. pylori transmission will inform strategies for preventing and treating new infections. The proposed research will also result in an improved understanding of the genetic diversification and adaptation of H. pylori to a new host, allowing the bacteria to maintain an active, persistent infection in the face of host defenses and eventually cause ulcers and stomach cancer.

描述（由申请人提供）：我的目标是成为研究细菌感染流行病学以及细菌遗传多样性在传播，发病机理和疾病结果中的作用的独立研究者。我设想我的研究计划将具有三个相互联系的臂：流行病学研究，涉及收集细菌样品，研究细菌样品的遗传多样性及其与临床和流行病学特征的关联，并研究观察到的遗传多样性的功能影响。我在进行细菌遗传多样性及其临床，流行病学和功能相关性的研究方面通过我的博士学位和迄今为止博士后培训获得了经验。但是，我尚未在进行流行病学研究方面有任何经验，这些研究涉及收集细菌样本和参与者数据，并认为这是我的培训和实现我的职业目标的主要差距。为了在培训中填补这一差距，我制定了一项研究建议，使我能够在设计参与者的流行病学研究，招募研究参与者的设计方面获得重要的经验，并收集生物标本和主题数据，并在有丰富经验经验的导师的指导下进行。 职业发展计划利用了培养跨学科研究的机构Fred Hutchinson Cancer Research Center（FHCRC）的教师之间的各种专业知识。拟议的研究将流行病学和分子生物学整合，将由一个指导委员会监督，其中包括分子和细胞生物学家和幽门螺杆菌专家（Nina Salama博士，导师），两位流行病学家（Johanna Lampe博士，Co-Mentor，Co-Mentor，Thomas Vaughan博士）和SARSTASIADIAN（SARHAH HOLTECIANSIAN）（thomas vaughan）（博士）。我将每周与我的导师会面，并至少每月两次与我的同事见面，讨论研究的细节。每年两次，我将与整个指导委员会会面，以介绍我​​的研究进度，并讨论我的研究和职业发展的未来步骤。除了我的指导委员会成员的支持外，我还将利用在FHCRC和华盛顿大学举行的科学和职业发展研讨会。 拟议的研究是对家庭内幽门螺杆菌传播的研究以及适应新宿主期间发生的细菌遗传变化。幽门螺杆菌的传播主要发生在家庭中，但尚不清楚这是否归因于家庭成员之间持续的密切接触，或者是因为家庭成员的遗传相关性促进了传播。对幽门螺杆菌长达几十年感染期间发生的单个宿主的细菌适应可能会导致菌株能够更好地定居在遗传上相似的宿主。幽门螺杆菌具有许多用于遗传多样化的机制，这可能有助于细菌适应传播后新感染的宿主。编码与宿主相互作用的幽门螺杆菌细胞表面结构的基因多样化在适应新宿主期间尤为重要。在这笔赠款中，检验了幽门螺杆菌传播主要发生在家庭内部的假设，因为适合单个宿主的幽门螺杆菌菌株可以更好地定居在遗传上相似的宿主。此外，我检验了以下假设：幽门螺杆菌在不相关的个​​体之间传播时将经历更多的遗传多样化。 AIM 1提议从具有生物儿童和有养育子女的基因型H.幽门的家庭的家庭成员那里收集粪便样本，并比较了幽门螺杆菌基因型共享的程度，这表明使用统计分析在两种不同类型的家族之间传播。在AIM 2中，将通过PCR和DNA测序比较从共享相同幽门螺杆菌菌株的家族成员中分离出的幽门螺杆菌DNA，以查找与细菌 - 宿主相互作用有关的基因的遗传变化，这些变化会影响编码蛋白的表达或功能。然后将检查幽门螺杆菌菌株对内的遗传变化程度，然后检查相关和无关的家庭成员共享。拟议的研究将导致有关家庭内幽门螺杆菌传播模式的重要信息，以及共享宿主遗传学与家庭接触传播的贡献。进一步了解幽门螺杆菌传播中涉及的因素将为预防和治疗新感染的策略提供信息。拟议的研究还将提高人们对幽门螺杆菌对遗传多样化和适应的理解 新宿主，使细菌在面对宿主防御的情况下保持活跃的持续感染，并最终导致溃疡和胃癌。