This application describes a 5-year training program for the development of a career in academic medicine. This application will allow the candidate to acquire extensive training in the area of reproductive and molecular biology and medicine through a unique integration of resources of the Wisconsin Primate Research Center and the Department of Pathology, and to address the research plan outlined below. This program will focus on the mechanisms of interaction of trophoblasts with uterine macrophages using rhesus monkey as a model. Dr. Golos, Associate Professor, Department of Obstetrics and Gynecology will mentor the Principal Investigator's performance. He is a recognized leader in the field of primate reproductive biology. To enhance the training, the program will include Dr. Malter, Professor of Pathology, as co-mentor and an expert in the molecular biology of cytokine expression. In addition, an advisory committee of highly regarded senior medical scientists will provide scientific and career advice. In this application, my central research hypothesis is that the interaction of decidual macrophages with extravillous trophoblasts can be mediated through interaction of the non-classical MHC class I molecule Mamu-AG, expressed on rhesus trophoblasts, with immunoglobulin-like transcript (ILT) receptors, expressed on macrophages. To test the hypothesis that the non-classical MHC class I molecule Mamu-AG can protect invading cytotrophoblasts from killing by macrophages through interaction with ILT2 and ILT4 receptors, I will address the following specific aims: 1) To characterize the distribution and immunophenotypes of rhesus monkey decidual macrophages and to develop successful methods for their isolation; 2) To clone ILT2 and ILT4 receptors from the rhesus monkey decidua, to produce soluble rhesus monkey ILT proteins and to produce monoclonal antibodies (mAbs) against these proteins; and 3) To assess whether Mamu-AG protects targets from killing by decidual macrophages through interactions with ILT2 and ILT4. The accomplishment of this plan will facilitate the candidate's transition to a career as an independent scientist, provide the candidate with a novel expertise in non-human primate reproductive physiology, and establish the basis for the development of an independent state-of-the art research program in molecular mechanisms of pregnancy pathology in humans and using experimental primate models.
