GENETIC CONTROL OF EARLY TESTICULAR DESCENT

描述：(改编自《调查者摘要》)在人群中 隐睾症发生在3%-4%的男性出生时，使这种异常 新生儿中最常见的先天出生缺陷。的两个主要后果 睾丸位置异常是由睾丸退行性变引起的不育。 精原细胞和成年后患恶性肿瘤的高风险。 睾丸发育过程中的下降是一个复杂的、多阶段的过程 男性的性腺向阴囊进发。在此过程的任何阶段都会失败 这一过程会导致隐睾症或隐睾症。长期的 这项建议的目标是确定控制 睾丸早期下降的分子机制。一只新鼠标 贝勒学院发现CRSP(带斑点的隐睾症)突变 医学，将作为一个模型系统来研究这一问题。雄性小鼠 CRSP纯合子患者的睾丸腹内位置较高， 与精子生成在早期阶段完全停止有关 扩散。初步数据显示，这种突变不会 特异性地影响精子发生，但在发育过程中睾丸下降。 它是由转基因插入到小鼠的端粒区域引起的 5号染色体导致染色体DNA的缺失。PI已经克隆了 将关键基因组区域转化为一系列重叠的BAC克隆并估计 删除的物理距离。本申请被设计成 验证CRSP突变扰乱早期 睾丸下降的决定因素和CRSP基因的故障可能 对变种人的隐睾症负责。具体目标是：1) 研究突变小鼠的分子-遗传重排；2) 识别位于关键区域内的基因；3)评估潜力 BAC基因在小鼠体内的克隆及表达 基因缺失突变体；4)鉴定和鉴定人CRSP基因。 由此得到的信息将为阐明这一功能提供一个框架 CRSP基因在隐睾症发病机制中的作用 与人类疾病相关的发育途径和新的 这种最常见的分娩的诊断工具和未来的治疗路线 男人的缺陷。

DESCRIPTION: (adapted from Investigator's abstract) 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 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, multistage 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 intraabdominal position of the testes, associated with complete arrest of spermatogenesis in the early stages of proliferation. Preliminary data has 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. The PI has 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 to 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 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; 4) to identify and characterize the human CRSP gene. 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 human disorder and development of new diagnostic tools and future therapeutic routes for this most common birth defect in men.