This proposal describes a rigorous five-year training program intended to facilitate the development of an independent academic career in reproductive medicine. The prinicipal investigator has completed a postdoctoral fellowship in the Laboratory of Perinatal Research (LPR) at The Ohio State University (OSU). Building upon this experience, this program has been designed to enable expansion of specific scientific skills through apprenticeship in the laboratories of several highly-regarded biomedical scientists. The program will focus on advanced training in the biological and biochemical aspects of inflammation, with specific emphasis on its role in human parturition. The principal investigator's scientific development will be mentored by members of an advisory committee. The sponsor, a well-respected reproductive biologist with expertise in the molecular aspects of term and preterm labor, has trained numerous clinical fellows, postdoctoral fellows, and graduate students. The clinical advisor is an authority on the clinical aspects of preterm labor. Each of the co-mentors was chosen based on extensive expertise in specific aspects of the research methodologies to be employed. The research will focus on defining the role of lipid bodies (LBs) in arachidonic acid (AA) storage, mobilization, and metabolism within cells of the amnion epithelium. The accumulation of numerous LBs with advancing gestation is a striking morphological feature of amniotic cells, although the role of these structures has not been clearly defined. In leukocytes and other cells associated with inflammation, LBs have been implicated in the storage of esterified AA. Furthermore, enzymes associated with the mobilization and oxidative metabolism of AA may be recruited to these structures. AA is the obligate precursor for the formation of the prostaglandins (PCs) considered critical to the process of parturition. The metabolic pathway leading to PG formation has been established; however, the physiological mechanisms that orchestrate this process remain incompletely defined. In part, this is due to the complexity of the system: PG biosynthesis is a highly dynamic and intimately regulated process, requiring the transient coupling of multiple enzymes (including phospholipases, cyclooxygenases, and PG synthase isoforms) that are otherwise segregated to different cellular compartments. The specific hypothesis to be tested is that amniotic cell LBs, by organizing the functional coupling between metabolic precursor (AA) and synthetic enzymes, may factor critically into the generation of PGs necessary for labor.
The specific aims i nclude: 1) determining the influence of labor on LB accumulation; 2) establishing the degree to which LBs associate with enzymes necessary for AA mobilization and metabolism; 3) determining the effects of LB perturbation on PG production; and 4) determining the effects of inhibited AA metabolism on LB formation. Specific experiments will involve complementary biochemical, molecular, immunological, and morphological assessments, which will significantly extend the laboratory skills of the trainee. The LPR at OSU provides an ideal environment for the training of physician-scientists, both in terms of resources and intellectual support. Through long-standing collaborative efforts between obstetrician-gynecologists and basic scientists from a variety of disciplines, the LPR serves as a unique platform for translational research. Training will be supplemented through rotations in two additional laboratories, each of which is fully equipped with the resources necessary to conduct the proposed studies, in addition to didactic graduate course work. ? ?
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