DE PEDIATRIC COBRE: DEVELOPMENTAL MECHANISMS OF UNDESCENDED TESTIS

隐睾症，或隐睾，是最常见的男性先天性异常之一，发生在2-4%的男孩。大多数情况下，它是非综合征性和单侧的，但通常与生殖细胞发育的双侧损伤和随后的不育和/或恶性肿瘤有关。这种复杂异质性疾病的生理学和发病机制尚不清楚，但现有数据表明存在多个易感基因座。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实验动物胚胎暴露后可引起隐睾症，人类隐睾症的表现很可能是基因-环境作用的结果 交互.在靶向缺失研究中，几个基因已被确定为隐睾症的强候选基因。这些包括insl 3、Great/LGR 8、Desrt/MRF 2、hoxA 10和hoxA 11。我们假设这些基因中的等位基因变异与隐睾症相关，并且这种风险受到胎儿激素环境的调节，这种环境可以通过遗传和外部环境因素进行改变。susceptibility.to本项目的总体目标是阐明大鼠模型中正常和异常睾丸下降的分子机制，并启动病例对照研究，以测量与人类隐睾症相关的效应和候选基因的生物标志物。具体目标是：（1）筛选候选基因 对于隐睾症，从差异表达研究和其他啮齿动物模型中鉴定，对于隐睾症大鼠模型中使用DHPLC和测序的突变;（2）启动隐睾症的病例对照研究，研究暴露和效应的生物标志物，包括（a）使用真实的时间RT-PCR的雄激素和雌激素受体的表达和（B）使用靶组织中精原细胞标志物的FACS分析的生殖细胞分化和（3）使用病例对照设计鉴定和研究隐睾症候选基因中的等位基因变异，该设计将通过传递不平衡测试来验证。这项工作的长期目标将是研究隐睾症病因学中的基因-环境相互作用，并识别，预测和尽可能减少导致这种常见疾病的风险因素。

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 are 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 to elucidate the molecular mechanisms of normal and abnormal testicular descent in a rat model 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) screen candidate genes for cryptorchidism, identified from differential expression studies and other rodent models, for mutations using DHPLC and sequencing in a rat model of cryptorchidism; (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 disequalibrium 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.