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利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 隐睾症，或隐睾症，是最常见的男性先天性畸形之一，发生在2%-4%的男孩中。在大多数情况下，它是非综合征和单侧的，但通常与双侧生殖细胞发育障碍以及随后的不孕和/或恶性肿瘤有关。这种复杂和异质性疾病的生理学和发病机制都不是很清楚，但现有的数据表明存在多个易感基因。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睾症。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，有几个基因被确定为隐睾症的有力候选基因。这些基因包括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，这种环境可以被遗传和外部环境因素改变。该项目的总体目标是阐明自发性隐睾症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，以测量与人类隐睾症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品系的差异表达研究，确定隐睾症的候选基因；(2)启动隐睾症的病例对照研究，以研究暴露和影响的生物标记物，包括(A)使用实时荧光RT-PCR技术研究雄激素和雌激素受体的表达；(B)利用流式细胞仪分析靶组织中的精原标志物，识别和研究生殖细胞分化；(3)采用病例对照设计，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检验得到验证。这项工作的长期目标将是研究隐睾症病因中的基因-环境相互作用，并识别、预测并在可能的情况下将导致这种常见疾病的风险因素降至最低。