Insulin-3 in Human Testicular Disease and as a Therapeutic Agent

描述(申请人提供)：睾丸下垂异常是儿科泌尿外科最常见的诊断之一。这笔赠款的总体目标是深入了解控制正常睾丸发育、睾丸下降及其在人类疾病中的作用的基因、蛋白质和激素信号网络。睾丸扭转是睾丸的自发旋转，可导致睾丸死亡，每4000名25岁以下的男性中就有一人受到影响。这可能是由于睾丸发育异常所致。此外，隐睾症，即睾丸从阴囊中消失，是男婴中最常见的生殖器异常，出生时影响3%。鉴于隐睾症的发病率越来越高，以及与睾丸扭转和隐睾症相关的频繁发生和显著的发病率，对睾丸发育机制的深入了解已经成为一个关键问题。新近发现的睾丸激素胰岛素-3(Insis)及其G蛋白偶联受体GREAT/LGR8对正常小鼠睾丸下降起着至关重要的作用。然而，这种荷尔蒙途径在人类中的作用还没有得到彻底的研究。为了解决这一需求，提出了3个具体目标：1)研究INIS和GREAT/LGR8在人类隐睾症中的功能意义；2)探索INIS信号改变作为小鼠和人类睾丸扭转的原因所起的作用；以及3)进行临床前小鼠研究INIS作为治疗隐睾症的药物治疗的作用。通过将使用基因工程小鼠模型的强大发育生物学基础科学与对受影响的人类的研究相结合，这项高度合作的研究的总体目标是促进我们对控制睾丸发育的激素途径的了解。

DESCRIPTION (provided by applicant): Abnormalities of testicular decent represent some of the most common diagnoses in pediatric urology. The overall objective of this grant is to gain insight into the genes, proteins and hormonal signaling networks that govern normal testicular development, testicular descent and their role in human disease. Testicular torsion, affecting 1 in 4,000 males younger than 25 years of age, is the spontaneous rotation of the testicle which can result in death of the testicle. This is likely due to abnormal testicular development. In addition, cryptorchidism, the absence of the testicle from the scrotum, is the most common genital anomaly of male infants affecting 3% at birth. Given the increasing incidence of cryptorchidism and the frequent occurrence and significant morbidity associated with testicular torsion and cryptorchidism, a deeper understanding of the mechanisms of testicular development has emerged a key issue. The recently identified testicular hormone lnsulin-3 (InsIS), and its recently identified G-protein coupled receptor, GREAT/LGR8, are crucial to normal murine testicular descent. However, the role of this hormonal pathway has not been thoroughly investigated in humans. To address this need, 3 specific aims are proposed: 1) To investigate the functional significance of InsIS and GREAT/LGR8 in human cryptorchidism; 2) To explore the role of altered InsIS signaling as a cause of testicular torsion in mice and humans; and 3) To perform preclinical murine studies investigating the role of InsIS as a drug therapy for the treatment of cryptorchidism. By integrating strong developmental biological basic science employing genetically engineered mouse models with research on affected humans, the overall goal of this highly collaborative investigation is to advance our knowledge of the hormonal pathways controlling testicular development.