Molecular Mechanism of Esophageal Diffused Leiomyomatosis

食管弥漫性平滑肌瘤病的分子机制

• 批准号: 09671309
• 负责人: OOHASHI Toshitaka
• 金额: $ 1.92万
• 依托单位: OKAYAMA UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09671309/
• 关键词: Alport syndrome; Leiomyomatosis; collagen IV; knockout mouse; 体細胞モザイク

We have investigated the molecular mechanism of diffused leiomyomatosis and the relationship of type IV collagen and smooth muscle cells differentiation and proliferation.We identified a DL/AS deletion and first characterization of the break point sequences. The results showed that the breakpoints share the same sequence, which is in turn closly homologous to the consensuses of topoisomerase I and II.The results implicate the genomic rearrangement responsible for the DL/AS phenotype and raise the possibility that there might be a third gene in interveaning sequence III that is involved in the regulation of smooth-muscle-cell proliferation.We have generated col4a6 null mice by introducing Neo^r gene into exon2 of col4a6 gene. The mice are fertile and did not show any obvious phenotype. Neither diffused leiomyomatosis in esophagus nor other tumors in smooth muscle organ were found in the mice which lived more than one year. This result exclude the possibility that deletion of col4a6 gene is a cause of DL.We are now investigating other possibilities by mating the col4a6 null mice and a transgemic mice which contains the partial genomic fragment delived5 from DL/AS patient. Also exon trapping was performed using a BAC contig which covers huge intron 2 of COL4A6 gene. These study were particularly relevant to the understunding of DL pathogenesis and its etiology.

我们研究了弥漫性平滑肌瘤病的分子机制以及IV型胶原与平滑肌细胞分化和增殖的关系。我们发现了一个DL/AS缺失，并首次对断点序列进行了表征。结果表明，这些断点具有相同的序列，而这又与拓扑异构酶I和拓扑异构酶II的一致性密切同源。这些结果暗示了导致DL/AS表型的基因组重排，并提出了在干预序列III中可能存在参与平滑肌细胞增殖调节的第三个基因的可能性。通过在col4a6基因外显子2中引入Neo^r基因，制备了col4a6基因缺失小鼠。这些小鼠是可育的，没有表现出任何明显的表型。寿命1年以上的小鼠未见食管弥漫性平滑肌瘤病及其他平滑肌器官肿瘤。这一结果排除了col4a6基因缺失导致DL的可能性。我们现在正在通过将col4a6基因缺失的小鼠与含有DL/AS患者部分基因组片段的转基因小鼠配对来研究其他可能性。此外，使用覆盖COL4A6基因巨大内含子2的BAC contig进行外显子捕获。这些研究对于了解DL的发病机制和病因尤为重要。

项目成果

Momota.R, et al.: "Two genes, COL4A3 and COL4A4 coding for the human α3(IV) and α4(IV) collagen chains are arranged head-to head on chromosome 2q36" FEBS Letters. 424. 11-16 (1998)

Momota.R 等人：“编码人类 α3(IV) 和 α4(IV) 胶原链的两个基因 COL4A3 和 COL4A4 在染色体 2q36 上头对头排列” FEBS Letters. 424. 11-16 (1998) ）

Raul Fleishmajer et al.: "There is Temporal and Spatial Expression of α1(IV),α2(IV),α5(IV),α6(IV) Collagen Chains and β1 Integrins During the Developoment・・・・" J Invest,Dermatol.109 (4). 527-533 (1997)

Raul Fleishmajer 等人：“在发育过程中存在 α1(IV)、α2(IV)、α5(IV)、α6(IV) 胶原链和 β1 整合素的时间和空间表达......”J Invest，Dermatol 。 109（4）527-533（1997）。

Ueki Y, et al: "Topoisomerase I and II consensus sequences in a 17-kb deletion junction of the COL4A5 and COL4A6 genes and immunohistochemical・・・" Am.J.Hum.Genet.62. 253-261 (1998)

Ueki Y 等人：“COL4A5 和 COL4A6 基因的 17 kb 缺失连接中的拓扑异构酶 I 和 II 共有序列和免疫组织化学……”Am.J.Hum.Genet.62 (1998)。

Coffey A J,Brooksbank R A,Brandau O,Oohashi T,Howell G R,Bye J M,Cahn A P,Durham J,et al.: "Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene." Nature Genet. 20. 129-135 (1998)

Coffey A J、Brooksbank RA、Brandau O、Oohashi T、Howell GR、Bye J M、Cahn A P、Durham J 等人：“X 连锁淋巴组织增生性疾病中宿主对 EBV 感染的反应是由 SH2 结构域编码基因突变引起的

Seki T.et al.: "Differential expression of type IV collagen isoforms, α5(IV) and α6(IV) chains, in basement membranes surrounding smooth muscle cells" Histochem.Cell Biol.110. 359-366 (1998)

Seki T. 等人：“平滑肌细胞周围基底膜中 IV 型胶原异构体、α5(IV) 和 α6(IV) 链的差异表达”Histochem.Cell Biol.110 (1998)。