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Neural induction of somatic stem cells / ES cells by VHL gene /peptide and application to regenerative medicine

VHL基因/肽对成体干细胞/ES细胞的神经诱导及其在再生医学中的应用

基本信息

批准号：
16390415
负责人：
KANNO Hiroshi
金额：
$ 8.59万
依托单位：
Yokohama City University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390415/
关键词：
somatic stem cell VHL protein protein transduction domain neural induction BC-box motif regenerative therapy neuronal disease peptide von Hipple-Lindau遺伝子

项目摘要

Several somatic stem cells have potential to differentiate to neurons, and they are hopeful to be used as grafted donor cells for neuronal regenerative therapy. However, the grated cells little survive and differentiate to functional neurons in recipient neural tissue. To overcome the problem, neural induction using neurotrophic factors or gene transfer has been employed before grafting, but neurotrophic factors do not occur specific neural induction, while gene transfer has risk of vector. If a neural induction domain for somatic stem cells exists in proteins to induce neural differentiation, its identification can contribute to neuronal regenerative therapy through neural induction of somatic stem cells using the neural induction domain. We previously demonstrated that von Hippel-Lindau tumor suppressor(VHL)protein has a function of neural induction in neural stem cells(NSCs)without any neurotrophic factors. Then, we hypothesized that a neural induction domain potentially exists in t … More he VHL protein. Here we identify a neural induction domain for somatic stem cells in the VHL protein, and show neural induction of the cells by transfer of the domain peptide linked to protein transduction domain(PTD). The neural induction domain in the VHL protein contains BC-box motif[(A,P,S,T)XX(A,C)XXX(A,I,L,V)]corresponding to binding site of elongin BC, which is evolutionary conserved from virus to mammalian.Therefore, we proposed that other BC-box proteins also contain the neural induction domain, and subsequently show to identify the neural induction domains at amino-acid sequences encoded by BC-box motif within BC-box proteins responsible for neural induction of somatic stem cells. In addition, we show that the domain has the same function for other somatic stem cells except for neural stem cells. Furthermore, when the domain peptide-transferred stem cells are grafted into recipient nervous tissue in neuronal disease models, the grafted cells differentiate to neurons and neuronal repair for neuronal disease models is achieved. Thus, a neural induction domain is identified at BC-box motif in BC-box proteins. The neural induction of somatic stem cells is caused by intracellular delivery of the neural induction domain peptide linked to PTD, and would contribute to neuronal regenerative therapy. Less

一些体干细胞具有向神经元分化的潜能，有望作为移植供体细胞用于神经元再生治疗。然而，移植的细胞在受体神经组织中很少存活并分化为功能性神经元。为了克服这一问题，在移植前采用神经营养因子或基因转移进行神经诱导，但神经营养因子不能发生特异性神经诱导，而基因转移存在载体风险。如果用于体干细胞的神经诱导结构域存在于蛋白质中以诱导神经分化，则其鉴定可有助于通过使用神经诱导结构域对体干细胞进行神经诱导的神经元再生治疗。我们以前证明，在没有任何神经营养因子的情况下，von Hippel-Lindau肿瘤抑制因子（VHL）蛋白在神经干细胞（NSCs）中具有神经诱导功能。然后，我们假设，一个神经感应域可能存在于t ...更多信息 VHL蛋白。在这里，我们确定了VHL蛋白中的体干细胞的神经诱导结构域，并显示了通过转移连接到蛋白转导结构域（PTD）的结构域肽对细胞的神经诱导。VHL蛋白中的神经诱导结构域含有BC-box基序[（A，P，S，T）XX（A，C）XXX（A，I，L，V）]，对应于elongin BC的结合位点，从病毒到哺乳动物，该位点在进化上是保守的，因此我们推测其他BC-box蛋白也含有神经诱导结构域，并随后显示在BC-1中由BC-盒基序编码的氨基酸序列处鉴定神经诱导结构域。负责体干细胞神经诱导的box蛋白。此外，我们表明，该结构域具有相同的功能，为其他体干细胞，除了神经干细胞。此外，当将结构域肽转移的干细胞移植到神经元疾病模型中的受体神经组织中时，移植的细胞分化为神经元，并且实现了神经元疾病模型的神经元修复。因此，在BC-box蛋白的BC-box基序处鉴定出神经诱导结构域。体干细胞的神经诱导是由与PTD连接的神经诱导结构域肽的细胞内递送引起的，并且将有助于神经元再生治疗。少