DE PEDIATRIC COBRE: DEVELOPMENTAL MECHANISMS OF UNDESCENDED TESTIS

DE PEDIATRIC COBRE：未降睾丸的发育机制

• 批准号: 6973096
• 负责人: Julia Spencer Barthold
• 金额: $ 16.29万
• 依托单位: ALFRED I. DU PONT HOSP FOR CHILDREN
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-07 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6973096
• 关键词: androgens; biomarker; cell differentiation; clinical research; cryptorchidism; flow cytometry; gene environment interaction; gene expression; genetic susceptibility; germ cells; high performance liquid chromatography; human subject; laboratory rat; linkage disequilibriums; pediatrics; polymerase chain reaction; spermatogenesis; steroid hormone receptor

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.

隐齿术或未降低的睾丸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，它是非综合性和单侧的，但通常与生殖细胞发育的双侧损害以及随后的不育和/或恶性肿瘤有关。这种复合物和异质性疾病的生理学和发病机理都没有充分了解，但可用的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胎儿暴露后会在实验动物中产生隐式术，人类疾病的表现可能是基因环境的结果 互动。在有针对性的缺失研究中，几个基因被确定为具有隐齿术的强大候选者。其中包括INSL3，Great/LGR8，DESRT/MRF2，HOXA10和HOXA11。我们假设这些基因中的等位基因变体与易感性有关。加密术，这种风险受到胎儿激素环境的调节，胎儿激素环境可以通过遗传和外部环境因素来改变。该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，并启动一项病例对照研究，以测量与人类隐鼠有关的效应生物标志物和候选基因的生物标志物。具体目标是：（1）屏幕候选基因 对于从差异表达研究和其他啮齿动物模型中鉴定出的隐齿术，用于使用DHPLC的突变并在密码术大鼠模型中进行测序； (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不平等测试。这项工作的长期目标将是研究隐式术病因中的基因 - 环境相互作用，并确定，预测，预测并在可能的情况下最大程度地减少对这种常见疾病的危险因素。