DE PEDIATRIC COBRE: DEVELOPMENTAL MECHANISMS OF UNDESCENDED TESTIS

DE PEDIATRIC COBRE：未降睾丸的发育机制

• 批准号: 7610722
• 负责人: Julia Spencer Barthold
• 金额: $ 15.9万
• 依托单位: ALFRED I. DU PONT HOSP FOR CHILDREN
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7610722
• 关键词: Androgen Antagonists; Androgens; Animals; Bilateral; Biological Markers; Candidate Disease Gene; Case-Control Studies; Cell Differentiation process; Childhood; Complex; Computer Retrieval of Information on Scientific Projects Database; Cryptorchidism; Data; Development; Disease; Endocrine disruption; Environmental Pollutants; Environmental Risk Factor; Estrogen Receptors; Estrogens; Etiology; Funding; Genes; Genetic; Genetic Variation; Germ Cells; Goals; Grant; Hormonal; Human; Impairment; Infertility; Institution; Malignant Neoplasms; Measures; Molecular; Pathogenesis; Perinatal Exposure; Personal Satisfaction; Physiology; Predisposition; Rat Strains; Rattus; Research; Research Personnel; Resources; Reverse Transcriptase Polymerase Chain Reaction; Risk; Risk Factors; Source; Testing; Time; Tissues; United States National Institutes of Health; Work; base; boys; case control; design; fetal; gene environment interaction; human disease; male; mutant; transmission process

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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 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胎儿暴露后可使实验动物产生隐睾。 人类疾病的表现很可能是基因-环境相互作用的结果。 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。 我们假设这些基因的等位基因变异与隐睾症的易感性有关，并且这种风险受到胎儿激素环境的调节，而胎儿激素环境可以通过遗传和外部环境因素来改变。 本项目的总体目标是阐明自发隐睾大鼠睾丸正常和异常下降的分子机制，并启动病例对照研究，以测量与人类隐睾相关的效应和候选基因的生物标志物。 具体目标是：（1）基于突变型和野生型大鼠品系的差异表达研究鉴定隐睾症的候选基因;（2）启动隐睾的病例对照研究，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进行验证。 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。