GENETIC CONTROL OF EARLY TESTICULAR DESCENT

早期睾丸下降的遗传控制

• 批准号: 6608246
• 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: 2002
• 资助国家: 美国
• 起止时间: 2002-05-01 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6608246
• 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.

在人类群体中，3%-4%的男性在出生时就会发生隐睾症，这使得这种异常成为新生儿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由精原细胞退化引起的不育和成年后患恶性肿瘤的高风险。在发育过程中，睾丸下降是一个复杂的、多阶段的过程，男性性腺向阴囊方向发展。在这一过程的任何阶段失败都会导致隐睾症或隐睾症。这项建议的长期目标是确定控制睾丸下降早期阶段的分子机制的关键遗传成分。贝勒医学院发现的一种新的小鼠突变CRSP(带斑点的隐睾症)将被用作研究这一问题的模型系统。CRSP纯合子雄性小鼠的睾丸腹内位置较高，与增殖早期完全停止精子生成有关。我们的初步数据表明，该突变不会特异性地影响精子发生，但会在发育过程中影响睾丸的下降。这是由于转基因插入小鼠5号染色体的端粒区域，导致染色体DNA缺失所致。我们已经将关键基因组区域克隆到一系列重叠的BAC克隆中，并估计了缺失的物理距离。目前的应用旨在检验这样一种假设，即CRSP突变破坏了睾丸下降的早期决定因素之一，CRSP基因的故障可能是突变的隐睾症的原因。其具体目的是：1)确定突变小鼠的表型和分子遗传重排；2)鉴定位于关键区的基因；3)通过BAC转基因拯救和基因缺失突变体的产生来评估小鼠潜在的候选基因。由此产生的信息将为阐明CRSP基因在隐睾症病因中的功能、确定与疾病相关的CRSP发育途径以及开发新的诊断工具和未来治疗这种男性最常见的出生缺陷提供一个框架。