This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.The process of differentiation plays a key role in generation of various cell types during peripheral nervous system (PNS) development. Perturbation in this process can lead to development of tumors such as neuroblastoma (NB), a childhood cancer. NB forms in the peripheral nerves that provide signals to organs such as the lungs and heart, and dictate the body's stress response. NB produces high levels of growth factors that promote tumor growth. One enzyme called dipeptidyl peptidase (DPPIV) that sits on cell surface is known to degrade these cancer-promoting growth factors. However, the role of DPPIV in development of PNS and NB is not known. Our work has shown that DPPIV is present in normal neural cells while almost absent in NB cells, suggesting that DPPIV is required for maintaining the normal state of the cells, and that its loss contributes to tumor development. In support of this idea, our studies show that restoration of DPPIV in NB cells causes them to become more like normal neurons and also leads to their death, thus suppressing their ability to form tumors in a mouse model. We will further investigate the regulation of DPPIV expression during PNS development in order to understand how DPPIV functions, using both cellular and mouse models. Completion of these studies should elucidate the important mechanism involved in PNS and NB development and may lead to the advancement of current treatment strategies to block growth of NB, which remains a leading cause of cancer death among children.
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