Significance of Notch1 and Tribbles-2 in macrophage fusion and granuloma formatio

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DESCRIPTION (provided by applicant): This application describes a 5-year training program for the development of an academic career in Dermatopathology. The PI has completed formal residency training in Anatomical Pathology at the Massachusetts General Hospital and Anatomical Pathology and Clinical Pathology at the University of Pennsylvania. He is now expanding his clinical skills in Dermatopathology and scientific skills in Notch signaling. Dr. Warren Pear, an international authority in Notch biology, will mentor the principal investigator's scientific development. Dr. Pear is an Associate Professor of Pathology and Laboratory Medicine and has mentored numerous students, post-doctoral fellows, and junior faculty members. To further promote the investigator's scientific development, an Advisory Committee comprising highly regarded scientists including Drs. Ellen Pure, Sarah Millar and John Seykora had been established. Dr. Seykora will also mentor the principal investigator's clinical development. The proposed research focuses on the role of Notch and Trib2 in macrophages, a key cellular component of chronic infectious and inflammatory disorders such as tuberculosis and schistosomiasis. Depending on the organs afflicted and the immune status of the host, these disorders can be chronically debilitating or life-terminating, especially in immunocompromised patients. Therefore, understanding the mechanisms underlying macrophage differentiation and granuloma formation is of particular importance to medicine, and designing novel therapeutics to modulate macrophage-dependent immune responses is of critical value. To this end, this application specifically focuses on the role of Notch and its target gene Trib2 in the differentiation of macrophages to multinucleate giant cells, a critical cell type in granulomas. Given the Mentor's expertise regarding the Notch and Trib2 molecules, Dr. Pear's laboratory provides an ideal setting to study the precise roles played by these molecules in macrophage biology. Specific Aims include: 1) determining the significance of Notch 1 signaling in macrophage fusion ex vivo, 2) studying the significance of Notch 1 signaling in macrophage fusion in vivo and 3) examining the significance of Trib2 in macrophage fusion. In summary, macrophages play a major role in chronic inflammatory disorders ranging in severity from chronically debilitating to life-terminating infectious disorders, especially those in immune compromised patients. This application aims to dissect the molecular mechanisms involved in macrophage fusion. The intellectual strength and academic track-record of the principal investigator's Mentor and Advisory Committee members, the available expertise in methods required to study gene regulation and cellular immunology, as well as the quality of the research facilities at the University of Pennsylvania Medical Center comprise an ideal environment in which to conduct this proposed training program.