P4-ROLE OF DIPEPTIDYL PEPTIDASE IV IN PERIPHERAL NEUROGENESIS AND NEUROBLASTOMAS

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 在周围神经系统（PNS）发育过程中，分化过程在各种细胞类型的产生中起着关键作用。在这个过程中的干扰可能导致肿瘤的发展，如神经母细胞瘤（NB），一种儿童癌症。NB在外周神经中形成，外周神经向肺和心脏等器官提供信号，并决定身体的应激反应。NB产生高水平的生长因子，促进肿瘤生长。已知一种位于细胞表面的称为二肽基肽酶（DPPIV）的酶可以降解这些促癌生长因子。然而，DPPIV在PNS和NB发展中的作用尚不清楚。我们的工作表明，DPPIV存在于正常神经细胞中，而在NB细胞中几乎不存在，这表明DPPIV是维持细胞正常状态所必需的，并且其丢失有助于肿瘤的发展。为了支持这一观点，我们的研究表明，NB细胞中DPPIV的恢复使它们变得更像正常神经元，并导致它们死亡，从而抑制它们在小鼠模型中形成肿瘤的能力。我们将进一步研究PNS发展过程中DPPIV表达的调节，以了解DPPIV如何发挥作用，使用细胞和小鼠模型。 这些研究的完成应该阐明参与PNS和NB发展的重要机制，并可能导致目前治疗策略的进步，以阻止NB的生长，NB仍然是儿童癌症死亡的主要原因。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for 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.