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

描述（由申请人提供）：睾丸脱落是小儿泌尿科最常见的诊断。这项资助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，影响1/4，000小于25岁的男性，是睾丸的自发旋转，可导致睾丸死亡。这可能是由于睾丸发育异常。此外，隐睾症，睾丸从阴囊中缺失，是男婴最常见的生殖器异常，在出生时影响3%。由于隐睾症的发病率不断增加，睾丸扭转和隐睾症的频繁发生和显着的发病率，更深入地了解睾丸发育的机制已经成为一个关键问题。最近发现的睾丸激素胰岛素-3（InsIS）及其最近发现的G蛋白偶联受体GREAT/LGR 8对正常小鼠睾丸下降至关重要。然而，这种激素途径的作用尚未在人类中得到彻底研究。为了解决这一需求，提出了3个具体目标：1）研究InsIS和GREAT/LGR 8在人类隐睾症中的功能意义; 2）探索改变的InsIS信号传导作为小鼠和人类睾丸扭转原因的作用; 3）进行临床前小鼠研究，研究InsIS作为治疗隐睾症的药物疗法的作用。通过整合强大的发育生物学基础科学，采用基因工程小鼠模型与受影响人类的研究，这项高度合作的研究的总体目标是提高我们对控制睾丸发育的激素途径的认识。

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.