FUNCTIONAL ROLE OF MDAZ IN INFERTILITY

描述：(改编自申请人的描述)：约10% 世界各地的夫妇都受到生育率下降和 这些病例中约有一半是由于没有产生精子所致。 (无精子症)。无精子症患者的细胞学分析 在相当大比例的病例中发现了Y染色体上的缺失 暗示了表型的遗传成分。这一地区曾被提议 含有无精子因子(AZF)。随后对该地区的分析 确定了三个不同的基因作为AZF候选基因，其中一个被命名为 在无精子症(DAZ)中删除。有趣的是，DAZ(MDAZ)的小鼠同源基因 是常染色体。小鼠mDAZ基因的纯合子破坏导致 精原阶段之后没有生殖细胞，这表明 DAZ/mDAZ在精子发生中的意义DAZ基因编码一种生殖细胞- 限制性胞质RNA结合蛋白。虽然DAZ的功能是 未知，它似乎调节一个靶基因的细胞质代谢(S) 在精子发生过程中必不可少的。尽管已经鉴定出DAZ基因， 其基因产物的功能及其如何对 无精子症是有限的，没有鉴定出同源的mrna底物。 它与之绑定并加以规范。我们最近设计了一种新的战略来 鉴定与RNA结合蛋白结合的天然同源基因。这项技术 使快速鉴定和克隆结合的特定细胞mRNA成为可能 RNA结合蛋白。这项建议的目标是确定自然的 与mDAZ蛋白(AIM-1)结合的基因(S)。 MDAZ调节这些靶基因的机制及其对 精子发生(AIM 2)。这将提供对功能的有价值的见解 DAZ在无精子症的发病机制中的作用，最终导致了 在受影响的个人中的治疗策略。了解这些功能是如何 通常在精子产生中起作用的蛋白质也将提供新的 男性避孕策略。

DESCRIPTION: (Adapted from applicant's description): Approximately 10% of couples world-wide are affected by reduced rates of fertility and approximately half of these cases result from the absence of sperm production (azoospermia) in males. Cytological analysis of patients with azoospermia identified a deletion on the Y chromosome in a significant proportion of cases implying a genetic component to the phenotype. This region was proposed to contain an Azoospermia Factor (AZF). Subsequent analysis of this region identified three distinct genes as AZF candidates one of which was termed Deleted in Azoospermia (DAZ). Interestingly, the mouse homologue of DAZ (mDAZ) is autosomal. Homozygous disruption of the mDAZ gene in mice results in the absence of germ cells beyond the spermatogonial stage demonstrating the significance of DAZ/mDAZ in spermatogenesis. The DAZ gene encodes a germ cell- restricted cytoplasmic RNA-binding protein. Although the function of DAZ is unknown, it appears to regulate the cytoplasmic metabolism of a target mRNA(s) essential in spermatogenesis. Despite the identification of the DAZ gene, progress into the function of its gene product and how it contributes to azoospermia is limited without identification of the cognate mRNA substrate that it binds to and regulates. We have recently devised a novel strategy to identify natural cognate mRNA bound by RNA-binding proteins. This technique enables rapid identification and cloning of specific cellular mRNA bound by an RNA-binding protein. The objective of this proposal is to identify the natural mRNA(s) which are bound by the mDAZ protein (AIM 1) and characterize the mechanism by which mDAZ regulates these target genes and how it contributes to spermatogenesis (AIM 2). This will provide valuable insight into the function of DAZ in the pathogenesis of azoospermia, eventually leading to the design of therapeutic strategies in affected individuals. Understanding how these proteins normally function in sperm production will also provide novel strategies in male contraception.