My long-term goal is to identify genes important to human gastrointestinal development. I have applied for the Physician Scientist Award because it is an ideal opportunity for me to obtain intensive training in molecular and developmental biology which I will require to conduct this type of research as an independent biomedical investigator. My goals for this award are to acquire the skills needed to study gut development, and to begin to do so using the zebrafish, Brachydanio rerio, a vertebrate uniquely suited to this purpose. To this end, Phase 1 involves both course work and particular projects that are suited at providing background in both developmental biology and genetics. The courses will include several offered by the Biochemistry Department at Harvard College. The laboratory project will be pursued in The MGH Developmental Biology Laboratory run by Dr. Mark C. Fishman. The focus of this lab is the use of genetic and molecular biological tools to dissect cell-cell interactions during early vertebrate development. Dr. Fishman is the director of the Cardiovascular Research Center, under whose auspices he has established a facility for the study of the zebrafish. Because of the transparency of the zebrafish embryo it is feasible to track the origin and migration of embryonic structures. During Phase 1 I will inject singly gut progenitor cells to determine the origin of the tubular gut, a process not trackable in the uterus of mammals. For the molecular genetic aspect of this project I will explore the 'enhancer-trap' and 'gene-trap' methods in the zebrafish, which are designed to capture genes of developmental interest and importance by their pattern of expression. Naturally, I will follow-up any specific gene of interest discovered by this methods, but if it proves efficient I will specifically use it to seek genes relevant to gut development as I proceed to Phase 2. My supervisory committee, to which I will provide at least an annual written project report, has been selected because of their involvement in these projects and special expertise, and will determine the appropriate time for progression to Phase 2. They include Wolfgang Driever, the zebrafish geneticist and developmental biologist, who is in the neighboring lab, Professor Douglas Melton, the expert in vertebrate development at Harvard, Dr. Daniel Podolsky, Chief GI Unit, MGH and Phase 2 sponsor and Dr. Mark C. Fishman.
|Pack, M; Solnica-Krezel, L; Malicki, J et al. (1996) Mutations affecting development of zebrafish digestive organs. Development 123:321-8|