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Deciphering von Hippel-Lindau (VHL/Vhl)-Associated Pancreatic Manifestations by Inactivating Vhl in Specific Pancreatic Cell Populations

机译:通过灭活特定胰腺细胞群中的Vhl来解密von Hippel-Lindau(VHL / Vhl)-相关的胰腺表现

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摘要

The von Hippel-Lindau (VHL) syndrome is a pleomorphic familial disease characterized by the development of highly vascularized tumors, such as hemangioblastomas of the central nervous system, pheochromocytomas, renal cell carcinomas, cysts and neuroendocrine tumors of the pancreas. Up to 75% of VHL patients are affected by VHL-associated pancreatic lesions; however, very few reports in the published literature have described the cellular origins and biological roles of VHL in the pancreas. Since homozygous loss of Vhl in mice resulted in embryonic lethality, this study aimed to characterize the functional significance of VHL in the pancreas by conditionally inactivating Vhl utilizing the Cre/LoxP system. Specifically, Vhl was inactivated in different pancreatic cell populations distinguished by their roles during embryonic organ development and their endocrine lineage commitment. With Cre recombinase expression directed by a glucagon promoter in α-cells or an insulin promoter in β-cells, we showed that deletion of Vhl is dispensable for normal functions of the endocrine pancreas. In addition, deficiency of VHL protein (pVHL) in terminally differentiated α-cells or β-cells is insufficient to induce pancreatic neuroendocrine tumorigenesis. Most significantly, we presented the first mouse model of VHL-associated pancreatic disease in mice lacking pVHL utilizing Pdx1-Cre transgenic mice to inactivate Vhl in pancreatic progenitor cells. The highly vascularized microcystic adenomas and hyperplastic islets that developed in Pdx1-Cre;Vhl f/f homozygous mice exhibited clinical features similar to VHL patients. Establishment of three different, cell-specific Vhl knockouts in the pancreas have allowed us to provide evidence suggesting that VHL is functionally important for postnatal ductal and exocrine pancreas, and that VHL-associated pancreatic lesions are likely to originate from progenitor cells, not mature endocrine cells. The novel model systems reported here will provide the basis for further functional and genetic studies to define molecular mechanisms involved in VHL-associated pancreatic diseases.
机译:von Hippel-Lindau(VHL)综合征是一种多形家族性疾病,其特征是发展为高度血管化的肿瘤,例如中枢神经系统的血管母细胞瘤,嗜铬细胞瘤,肾细胞癌,囊肿和胰腺的神经内分泌肿瘤。多达75%的VHL患者受到VHL相关的胰腺病变的影响;然而,已发表文献中很少有报道描述胰腺中VHL的细胞起源和生物学作用。由于小鼠体内Vhl的纯合缺失会导致胚胎致死性,因此本研究旨在通过利用Cre / LoxP系统有条件地使Vhl失活来表征VHL在胰腺中的功能重要性。具体而言,Vhl在不同的胰腺细胞群体中被灭活,它们在胚胎器官发育过程中的作用及其内分泌谱系的承诺得以区分。通过由胰高血糖素启动子在α细胞中或胰岛β细胞中的胰岛素启动子指导的Cre重组酶表达,我们表明Vhl的缺失对于内分泌胰腺的正常功能是必不可少的。另外,终末分化的α细胞或β细胞中VHL蛋白(pVHL)的不足不足以诱导胰腺神经内分泌肿瘤发生。最重要的是,我们提出了第一个缺乏pVHL的小鼠中与VHL相关的胰腺疾病的小鼠模型,该模型利用Pdx1-Cre转基因小鼠使胰腺祖细胞中的Vhl失活。在Pdx1-Cre; Vhl f / f纯合小鼠中形成的高度血管化的微囊腺瘤和增生胰岛表现出与VHL患者相似的临床特征。在胰腺中建立三种不同的细胞特异性Vhl基因敲除基因,使我们能够提供证据,表明VHL对产后导管和外分泌胰腺具有重要的功能,并且与VHL相关的胰腺病变很可能起源于祖细胞,而不是成熟的内分泌细胞。本文报道的新型模型系统将为进一步的功能和遗传研究提供基础,以定义与VHL相关的胰腺疾病涉及的分子机制。

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