Genetic basis of testicular descent

描述（由申请人提供）：隐睾症，或隐睾，是新生男孩最常见的先天性缺陷之一。 如果不及时治疗，这种情况会导致不育，并大大增加成年后患睾丸癌的机会。 该项目的主要目的是建立发育过程中睾丸下降的遗传和生化事件的精确网络。 该建议是基于最近确定的睾丸激素胰岛素样3，及其受体，伟大的，作为引带分化的关键调节剂。 使用小鼠crsp突变体，我们已经确定了GREAT基因，表明它编码G蛋白偶联受体，并证明GREAT是体内INSL 3的唯一同源受体。 隐睾患者的两个基因的突变分析显示功能有害的突变，这可能是负责异常表型。 在我们的实验室中产生的一系列转基因小鼠突变体提供了一个独特的基础，以解决特定的问题，在体内的作用和机制的INSL 3信号。 此外，INSL 3受体是GPCR的事实使其成为未来治疗开发的有吸引力的靶标。 我们将探讨这一假设，即INSL 3信号通路是睾丸下降的关键调节因子。 为了验证这一假设，我们提出了以下具体目标1：鉴定在发育过程中导致INSL 3/GREAT表达激活的遗传因素; 2。确定INSL 3调控的下游靶基因; 3.确定参与INSL 3/GREAT信号传导的细胞通路; 4. 确定GREAT受体激活及其脱敏的机制。 因此，我们将确定一系列导致睾丸下降的遗传事件，并表征INSL 3/GREAT细胞信号传导的机制。 拟议的研究将更好地了解睾丸下降及其在男性发育过程中的调节。

DESCRIPTION (provided by applicant): Cryptorchidism, or undescended testis, is one of the most common congenital defect in newborn boys. If left untreated, this condition causes infertility and drastically increases the chance of testicular cancer in adulthood. The key aim of this project is to establish the precise network of genetic and biochemical events underlying testicular descent during development. The proposal is based on recent identification of the testicular hormone Insulin-like 3, and its receptor, GREAT, as the critical regulators of gubernacular differentiation. Using mouse crsp mutant we have identified the GREAT gene, showed that it encodes a G protein-coupled receptor, and demonstrated that GREAT is the only cognate receptor for INSL3 in vivo. Mutation analysis of the two genes in cryptorchid patients revealed functionally deleterious mutations, which may be responsible for the abnormal phenotype. A series of transgenic mouse mutants produced in our laboratory provides a unique basis to address specific questions regarding the role and mechanisms of INSL3 signaling in vivo. Furthermore, the fact, that the INSL3 receptor is a GPCR, makes it an attractive target for future therapeutic development. We are going to explore the hypothesis, that INSL3 signaling pathway is a key regulator of testicular descent. To test this hypothesis we propose the following Specific Aims 1: To identify genetic factors leading to the activation of INSL3/GREAT expression during development; 2. To identify downstream target genes controlled by INSL3; 3. To identify cellular pathways involved in INSL3/GREAT signaling; 4. To determine mechanisms of GREAT receptor activation and its desensitization. As a result, we will identify a sequence of genetic events leading to testicular descent and characterize the mechanisms of INSL3/GREAT cellular signaling. The proposed studies will provide a better understanding of the testicular descent and its regulation during male development.