DE PEDIATRIC COBRE: DEVELOPMENTAL MECHANISMS OF UNDESCENDED TESTIS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。隐睾症，或称隐睾，是最常见的男性先天性异常之一，发生在2-4%的男孩中。在大多数情况下，它是无综合征和单侧的，但通常与双侧生殖细胞发育障碍和随后的不孕症和/或恶性肿瘤有关。这种复杂和异质性疾病的生理和发病机制尚不清楚，但现有数据表明存在多个易感位点。此外，雌激素、抗雄激素和许多具有内分泌干扰作用的环境污染物在胎儿接触后会使实验动物产生隐睾。人类疾病的表现很可能是基因与环境相互作用的结果。在靶向缺失研究中，一些基因已被确定为隐睾症的有力候选基因。这些包括insl3， Great/LGR8, desert /MRF2， hoxA10和hoxA11。我们假设这些基因中的等位基因变异与隐睾的易感性有关，并且这种风险受胎儿激素环境的调节，而胎儿激素环境可以被遗传和外部环境因素改变。本项目的总体目标是阐明自发性隐睾大鼠正常和异常睾丸下降的分子机制，并启动一项病例对照研究，以测量与人类隐睾相关的生物标志物和候选基因。具体目标将是：(1)基于突变型和野生型大鼠菌株的差异表达研究，确定隐睾症的候选基因；(2)启动隐睾症的病例对照研究，研究暴露和影响的生物标志物，包括(a)使用实时RT-PCR分析雄激素和雌激素受体的表达，(b)使用FACS分析靶组织中精原标记的生殖细胞分化，(3)使用病例对照设计识别和研究隐睾症候选基因的等位基因变异，并将通过传播不平衡测试验证。这项工作的长期目标将是研究隐睾病因学中的基因-环境相互作用，并识别、预测并在可能的情况下尽量减少导致这种常见疾病的危险因素。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cryptorchidism, or undescended testis, is one of the most common male congenital anomalies, occurring in 2-4% of boys. It is non-syndromic and unilateral in the majority of cases, yet is often associated with bilateral impairment of germ cell development and subsequent infertility and/or malignancy. Neither the physiology nor the pathogenesis of this complex and heterogeneous disease is well understood but available data suggest the presence of multiple susceptibility loci. In addition, estrogens, antiandrogens and many environmental pollutants with endocrine-disrupting effects produce cryptorchidism in experimental animals after fetal exposure. It is likely that manifestation of the human disease is the result of gene-environment interactions. Several genes have been identified as strong candidates for cryptorchidism in targeted deletion studies. These include insl3, Great/LGR8, Desrt/MRF2, hoxA10 and hoxA11. We hypothesize that allelic variants in these genes are associated with susceptibility to cryptorchidism and that this risk is modulated by the fetal hormonal milieu, which can be altered by genetic as well as extrinsic environmental factors. The overall goals of this project are to elucidate the molecular mechanisms of normal and abnormal testicular descent in spontaneously cryptorchid rats and to initiate a case-control study to measure biomarkers of effect and candidate genes that are associated with human cryptorchidism. Specific aims will be to: (1) identify candidate genes for cryptorchidism based on differential expression studies of mutant and wild type rat strains; (2) initiate a case-control study of cryptorchidism to study biomarkers of exposure and effect including (a) expression of androgen and estrogen receptors using real time RT-PCR and (b) germ cell differentiation using FACS analysis of spermatogonial markers in target tissues and (3) identify and study allelic variants in candidate genes for cryptorchidism using a case-control design that will be validated by transmission disequilibrium testing. The long-term goals of this work will be to study gene-environment interaction in the etiology of cryptorchidism and to identify, predict and, when possible, minimize risk factors that contribute to this common disease.