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Establishment of recovery spermatogenesis after chemotherapy due to the microenvironment modulation in seminiferous tubule

曲细精管微环境调节化疗后恢复精子发生的建立

基本信息

批准号：
17591670
负责人：
KOH Eitetsu
金额：
$ 2.37万
依托单位：
Kanazawa University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

项目摘要

As a result of having retrieving genetic information from NCBI, a gene which was damaged selectively due to the various anti-cancer agents has been selected. Moreover recovery-related proteins after treating using anti-cancer agents were also associated with the genes during expressing in the meiotic stage. These candidate genes contributed to spermatogenesis and were naive to various anti-cancer agents depended on their dose. Generally speaking, the most important process of meiotic stage is accurate distribution of homologous chromosomes. It is assumed that the homologous recombination between chromosomes occurred initially in a transient DNA double-strand break (DSB) in the beginning to meiotic stage. In the cross reaction between homologous strands, the proteins such as Rad51 or Rad52, Rad54, Rad55, Rad57, DMC1, Rpa1 play a central role in a eukaryote. Specially, it is reported that RAD51 has not replaced the function of DMC1 (GenBank, NM_007068) in meiotic stage according to the knockout mouse. The transcripts of DMC1 are particularly specific in meiotic stage and enable to recognize only homogenous strands.Our study revealed that the transcripts of DMC1 were existed three products derived from alternative splicing. Clinically these transcripts had a various number in the idiopathic male infertility. According to analyzing the clinical samples, it was suggested that the number of the isoforms leaded to modify a motif and domain of the DMC1, and was thought to be induced apoptosis of spermatid. These genetic splicing variants contributed to meiotic control and clarified to affect the possibility of the spermatogenesis. Our study showed that one mechanism of spermatogenesis arrests was associated with the dysfunction of early stage during meiosis due to isofoms derived from domain specific proteins.

作为从NCBI检索遗传信息的结果，已经选择了由于各种抗癌剂而被选择性损伤的基因。此外，抗癌药物治疗后的恢复相关蛋白也与减数分裂期表达的基因相关。这些候选基因有助于精子发生，并且对各种抗癌药物不敏感，这取决于它们的剂量。一般来说，减数分裂阶段最重要的过程是同源染色体的准确分布。推测染色体间的同源重组最初发生在减数分裂初期的短暂DNA双链断裂（DSB）中。在同源链之间的交叉反应中，诸如Rad51或Rad52、Rad54、Rad55、Rad57、DMC 1、Rpa1等蛋白质在真核生物中起核心作用。特别是，根据敲除小鼠的研究，发现RAD 51在减数分裂阶段并没有取代DMC 1（GenBank，NM_007068）的功能。DMC1的转录本在减数分裂期特异性很强，只能识别同源的单链，我们的研究表明DMC1的转录本存在三种选择性剪接产物。在临床上，这些转录本在特发性男性不育症中有不同的数量。通过对临床标本的分析，推测其亚型的增多可能导致DMC 1的一个基序和结构域发生改变，并可能诱导精子细胞凋亡。这些基因剪接变异体参与了减数分裂的调控，并阐明了影响精子发生的可能性。我们的研究表明，精子发生停滞的一种机制与减数分裂早期阶段的功能障碍有关，这是由于来自结构域特异性蛋白质的异构体造成的。