GENETIC CONTROL OF EARLY TESTICULAR DESCENT

早期睾丸下降的遗传控制

• 批准号: 6331737
• 负责人: Alexander I Agoulnik
• 金额: $ 17.58万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-10 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6331737
• 关键词: cryptorchidism; disease /disorder model; fertility; gene mutation; genetic regulation; genetically modified animals; laboratory mouse; male

In human populations cryptorchidism occurs in 3-4% of males at birth, making this abnormality the most frequent congenital birth defect in newborn boys. Two main consequences of an abnormal of an abnormal location of the testis are infertility caused by degeneration of the spermatogonial cells and a high risk of malignant tumors in adulthood. Testicular descent during development is a complex, multi-stage process whereby the male gonads progress toward the scrotum. Failure in any stage of this process results in cryptorchidism or undescended testis. The long-term objectives of this proposal are to identify key genetic components that control the molecular mechanisms of the early phases of testicular descent. A new mouse mutation, crsp (cryptorchidism with spotting), discovered in Baylor College of Medicine, will be used as a model system to study this problem. Male mice homozygous for crsp have a high intra abdominal position of the testes, associated with complete arrest of spermatogenesis in the early stages of proliferation. Our preliminary data have shown that the mutation does not specifically affect spermatogenesis but testicular descent during development. It is caused by a transgene insertion into the telomeric region of mouse chromosome 5 producing a deletion of the chromosomal DNA. We have cloned the critical genomic region into a series of overlapping BAC clones and estimated the physical distance of the deletion. The present application is designed to test the hypothesis that the crsp mutation disrupts one of the early determinants of testicular descent and that malfunction of the crsp gene could be responsible for the cryptorchidism in mutant. The specific aims are: 1) to characterize the phenotype and the molecular genetic rearrangements in the mutant mice; 2) to identify genes residing within the critical region; 3) to evaluate potential candidate genes in mouse by BAC transgenic rescue and generation of gene deficient mutants. The resulting information will provide a framework for elucidating the function of the CRSP gene in the etiology of cryptorchidism, determination of the CRSP developmental pathways relevant to the disorder and development of new diagnostic tools and future therapeutic routes for this most common birth defect in men.

在人类中，隐睾症在出生时发生在3-4%的男性中，使这种异常成为新生男孩中最常见的先天性出生缺陷。睾丸位置异常的两个主要后果是精原细胞变性引起的不育和成年后患恶性肿瘤的高风险。睾丸下降在发展过程中是一个复杂的，多阶段的过程，其中男性性腺进展到阴囊。任何一个阶段的失败都会导致隐睾或隐睾。该提案的长期目标是确定控制睾丸下降早期分子机制的关键遗传成分。在贝勒医学院发现的一种新的小鼠突变，crsp（隐睾与斑点），将被用作研究这个问题的模型系统。crsp纯合雄性小鼠的睾丸位于腹腔内较高位置，这与精子发生在增殖早期阶段的完全停滞有关。我们的初步数据表明，该突变并不专门影响精子发生，但在发育过程中睾丸下降。它是由转基因插入到小鼠5号染色体端粒区产生染色体DNA缺失引起的。我们已经将关键基因组区域克隆到一系列重叠BAC克隆中，并估计了缺失的物理距离。本申请被设计用于检验以下假设：crsp突变破坏睾丸下降的早期决定因素之一，并且crsp基因的功能障碍可能是突变体中隐睾症的原因。具体目标是：1）鉴定突变小鼠的表型和分子遗传重排; 2）鉴定存在于关键区域内的基因; 3）通过BAC转基因拯救和产生基因缺陷突变体来评估小鼠中潜在的候选基因。由此产生的信息将提供一个框架，阐明CRSP基因在隐睾症病因学中的功能，确定CRSP发育途径相关的疾病和发展新的诊断工具和未来的治疗途径，这种最常见的男性出生缺陷。