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.
Helicobacter pylori causes ulcers and stomach cancer in a subset of those who are infected. The proposed research will result in important information about the patterns of H. pylori transmission within families and adaptation of H. pylori to a new host. Further knowledge of the factors involved in H. pylori transmission and its ability to maintain an active, persistent infection in the face of host defenses will inform strategies for preventing and treating new infections.