A program has been created to guide the candidate's development as an independent investigator based in a long-term interest in pulmonary defense mechanisms and a strong background in molecular and cell biology and in clinical medicine. Dr. Fishman has built on majors in immunopathology and biology and training at Johns Hopkins University School of Medicine, developing novel models for research on pulmonary defenses, atherogenesis, and renal cellular injury. His clinical training and a fellowship in molecular biology at the Massachusetts General Hospital (MGH) have prepared him for a medical staff position. His research interests were sparked by a growing population of immunocompromised patients, notably those with the Acquired Immune Deficiency Syndrome (AIDS). Pneumocystis carinii (PC) develops uniquely on the alveolar epithelium in these hosts, including over 50% of AIDS patients. We propose to study the interaction of alveolar Type I and II cells with PC at the cellular and molecular levels. PC has been grown in vivo and amplified in vitro. PC-specific proteins, antisera, and nucleic acids have been isolated. The proposed research program will (1) study the morphology of binding of cultured alveolar epithelial cells to PC; (2) identify these (glyco-) proteins and antigens of rat and human PC; (3) clone the major surface antigens of PC in a lambda bacteriophage expression system (GT11); (4) use the cloned proteins to define the epithelial-PC interaction. PC-specific proteins and nucleic acids may also allow new noninvasive diagnostic techniques. This work will address important questions about the pulmonary-parasite interaction in the alveolus. It will also provide the basis for an ongoing exchange between the candidate and the program's sponsors and consultants. In addition to a primary commitment to basic research training on a topic of clinical importance, the program will utilize regular laboratory data sessions, seminars and advanced coursework to integrate and supplement the candidate's scientific training. Regular periods of clinical responsibility and teaching are planned. In this plan, Dr. Fishman will utilize his unique background, a well-equipped research laboratory and the specialized facilities and staff in Infectious Disease, Pulmonary and Molecular Biology at the MGH, and in Pathology and Tropical Medicine at Harvard. The individuals and the institution sponsoring Dr. Fishman's application have made commitments to guide and support the candidate during his professional development.
