This proposal describes a training program for the development of a career as a clinician scientist. The principal investigator has trained in Pediatric Hematology Oncology at Memorial Sloan Kettering Cancer Center and now will expand her skills through an integrated research program. The program will expand the cellular biology approaches the applicant has acquired and add molecular biology knowledge and methodologies. Dr. Howard Petrie will mentor the principal investigator's scientific development. Dr. Petrie is a recognized expert in the field of T cell development with a laboratory devoted to both cellular and molecular approaches to understanding the adult steady state thymus. This aspect of the program will be augmented by a didactic component. To enhance the training, the program will enlist the expertise of Dr. Richard O'Reilly, Chairman of Pediatrics and Bone Marrow Transplantation. Dr. O'Reilly is a recognized expert in bone marrow transplant, immunodeficiency and mouse models for transplant. In addition, an advisory committee of highly regarded scientists and physician-scientists will provide scientific and career advice. The project will focus on the role of thymic stroma in supporting T lymphocyte reconstitution. Recent work in the mentor's lab has developed a model system in which thymic reconstitution occurs without prior myeloablative or immunosuppressive agents. This model will be used to identify cytotoxic damage to thymic stroma that impairs stromal support of de novo T cell development. The specific aims include: 1) Determining which agents impair stromal support of T cell development, 2) Identifying which stromal cells are targeted by these agents, and 3) Determining the molecular mechanisms responsible for impaired support of T cell development. It is anticipated that this approach will add to the understanding of normal T cell development. This is also a novel and systematic way to identify treatment related effects on T cell immune reconstitution. By incorporating expertise from diverse resources, the departments of Immunology at Sloan Kettering Institute and Pediatrics at MSKCC provide an ideal setting for training physician-scientists. Such a setting provides a scientific and clinical basis from which to launch an academic career. [unreadable] [unreadable]