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

P4-二肽基肽酶 IV 在外周神经发生和神经母细胞瘤中的作用

• 批准号: 8168062
• 负责人: UMADEVI V WESLEY
• 金额: $ 22.11万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8168062
• 关键词: Biology; Cell Death; Cell Differentiation process; Cell surface; Cells; Cessation of life; Child; Computer Retrieval of Information on Scientific Projects Database; Development; Dipeptidyl Peptidases; Embryo; Enzymes; Fibroblast Growth Factor; Fibroblast Growth Factor 2; Funding; Gene Expression; Grant; Growth and Development function; Institution; Lead; Malignant Childhood Neoplasm; Malignant Neoplasms; Molecular Profiling; Mus; Neoplasm Metastasis; Neural Crest; Neuroblastoma; Neurons; Peptides; Peripheral; Process; RNA Interference; Research; Research Personnel; Resources; Role; Signal Transduction; Source; Therapeutic; United States National Institutes of Health; Western Blotting; Work; improved; inhibitor/antagonist; insight; neurogenesis; notch protein; restoration; tumor; tumor growth

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. Perturbations in the normal differentiation process during neural crest development can lead to development of tumors such as neuroblastoma (NB), a fatal childhood cancer. Treatment options for children with advanced NB remain limited as NB biology is not well understood. We and others have identified one enzyme called dipeptidyl peptidase (DPPIV) that sits on cell surface and degrades cancer-promoting peptides. Our work has shown that DPPIV is present in normal neural cells while absent in NB cells, suggesting that DPPIV loss contributes to tumor development. Indeed we have demonstrated that restoration of DPPIV in NB cells reverses them towards normal neurons leading to their death, thus suppressing their tumor forming ability. NB cells produces excess levels of Notch receptor 3 and basic FGF that promote tumor growth and survival. Our current studies using gene expression profiles and western blot analysis show that restoration of DPPIV in NB cells decreases levels of Notch3 and the bFGF leading to NB cell differentiation and death. Inhibition of Notch3 and bFGF signaling using RNA interference and pharmacological inhibitors also leads to NB cell death, further demonstrating the importance of blocking Notch3 and bFGF function to suppress NB growth and development. Furthermore, our initial studies show that DPPIV expression is associated with onset of mature differentiated neurons as seen in developing mouse embryos. Overall, our studies not only contribute to the better understanding of NB biology but also provide new insights for developing improved therapeutic approaches to disrupt signals that promote tumor growth and metastasis.

这个子项目是许多研究子项目中的一个 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来源获得了主要资金， 因此可以在其他CRISP条目中表示。列出的机构为 研究中心，而研究中心不一定是研究者所在的机构。 神经嵴发育过程中正常分化过程的扰动可能导致肿瘤的发展，如神经母细胞瘤（NB），一种致命的儿童癌症。晚期NB儿童的治疗选择仍然有限，因为NB生物学尚未得到很好的理解。我们和其他人已经确定了一种称为二肽基肽酶（DPPIV）的酶，它位于细胞表面并降解促癌肽。 我们的工作表明，DPPIV存在于正常神经细胞中，而在NB细胞中不存在，这表明DPPIV丢失有助于肿瘤的发展。 事实上，我们已经证明，NB细胞中DPPIV的恢复使它们向正常神经元逆转，导致它们死亡，从而抑制它们的肿瘤形成能力。 NB细胞产生过量的Notch受体3和碱性FGF，促进肿瘤生长和存活。我们目前使用基因表达谱和蛋白质印迹分析的研究表明，NB细胞中DPPIV的恢复降低了Notch 3和bFGF的水平，导致NB细胞分化和死亡。使用RNA干扰和药理学抑制剂抑制Notch 3和bFGF信号传导也导致NB细胞死亡，进一步证明阻断Notch 3和bFGF功能对抑制NB生长和发育的重要性。此外，我们的初步研究表明，DPPIV表达与成熟分化的神经元的发生有关，如在发育中的小鼠胚胎中所见。总的来说，我们的研究不仅有助于更好地了解NB生物学，而且还为开发改进的治疗方法提供了新的见解，以破坏促进肿瘤生长和转移的信号。