Molecular Medicine of Neurodegenerative Disease and Malignant Tumor

1.为了研究酪氨酸1062在RET神经元分化中的作用，我们产生了敲入小鼠，其中酪氨酸1062被苯丙氨酸取代。小鼠整个肠道的肠神经元分化严重受损，表明通过酪氨酸1062的细胞内信号传导在肠神经系统的发育中起重要作用.中期因子（MK）受体被认为是蛋白聚糖（包括蛋白酪氨酸磷酸酶ζ（PTPζ）和多配体聚糖）的分子复合物。MK以高亲和力结合PTP β的硫酸软骨素部分，特别是结合具有4，6-二硫酸化N-乙酰半乳糖胺的E单元。MK与syodecan的结合是通过N-和6-O-硫酸氨基葡萄糖和2-硫酸糖醛酸的三硫酸化结构介导的. Dorfin是一种RING指型E3泛素连接酶，主要定位于家族性ALS的包涵体中，具有铜/锌超氧化物歧化酶（SOD 1）突变以及 关于我们 散发性肌萎缩侧索硬化症。Dorphin生理上结合和泛素化来自家族性ALS患者的各种SOD 1突变体，并增强其降解。Dorfin的过表达可以保护突变SOD 1对神经细胞的毒性作用，减少SOD 1的包涵体.通过交配单基因突变体产生缺乏GM 2/GD 2和GD 3合酶基因的双敲除小鼠。我们观察到一个难治性皮肤病变，出现在脸上的突变小鼠在出生后25周或更晚。在损伤部位的表皮和表皮下发现特征性的神经纤维增生，可能是连续皮肤损伤的结果。在幼年突变小鼠中观察到周围神经变性，提示感觉功能下降导致过度抓挠。用透明质酸（HA）处理QG 90人肺癌细胞强烈激活MMP-2的分泌，在QG 90细胞中表达反义CD 44 s抑制HA依赖的MMP-2的分泌。我们发现HA-CD 44信号在HA依赖的MMP-2分泌中起关键作用，因此，在QG 90细胞的侵袭性中起关键作用。少

1. To investigate the role of tyrosine 1062 in RET in neuronal differentiation, we produced knock-in mice in which tyrosine 1062 was replaced with phenylalanine. Differentiation of enteric neurons in the whole intestinal tract was severely impaired in mice, indicating that the intracellular signaling via tyrosine 1062 plays an important role in the development of the enteric nervous system.2. The midkine (MK) receptor is thought to be a molecular complex of protepglycans including protein tyrosine phosphatase ζ (PTPζ) and syndecan. MK binds to the chondroitin sulfate portion of PTPζ, especially to the E unit that has 4,6-disulfated N-acetylgalactosamine, with high affinity. The binding of MK to syodecan was mediated by the trisulfated structure of N- and 6-O-sulfated glucosamine and 2-sulfated uronic acid.3. Dorfin, a RING finger-type E3 ubiquitin ligase, is predominantly localized in the inclusion bodies of familial ALS with a copper/zinc superoxide dismutase (SOD1) mutation as well a … More s sporadic ALS. Dorphin physiologically bound and ubiquitylated various SOD1 mutants derived from familial ALS patients and enhanced their degradation. The overexpression of Dorfin protected against the toxic effects of mutant SOD1 on neural cells and reduced SOD1 inclusions.4. Double knock-out mice lacking the GM2/GD2 and the GD3 synthase gene were generated by mating single gene mutants. We observed a refractory skin lesion that appeared on the face of mutant mice at 25 weeks after birth or later. Characteristic proliferation of nerve fibers was found in the epidermis and subepidermis at the injured sites, probably a result of continuous skin injury. Peripheral nerve degeneration was observed in young mutant mice, suggesting that reduced sensory function induced over-scratching.5. Treatment of QG90 human lung cancer cells with hyaluronan (HA) strongly activated MMP-2 secretion and expression of antisense CD44s in QG90 cells inhibited the HA-dependent secretion of MMP-2. We found that HA-CD44 signaling plays a key role in the HA-dependent secretion of MMP-2 and, hence, in the invasiveness of QG90 cells. Less