Insulin-3 in Human Testicular Disease

描述（由申请人提供）：睾丸异常是儿科泌尿科最常见的诊断之一。这项拨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。睾丸扭转是指睾丸自发旋转，可导致睾丸死亡，每4 000名25岁以下男性中就有1人患有睾丸扭转。这可能是由于睾丸发育异常。此外，隐睾，即阴囊内睾丸缺失，是男性婴儿最常见的生殖器异常，出生时发病率为3%。鉴于隐睾的发病率不断上升，且与睾丸扭转和隐睾相关的发病率频繁且显著，深入了解睾丸发育的机制已成为一个关键问题。最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至关重要。然而，这种激素通路在人类中的作用尚未得到彻底的研究。为了解决这一需求，提出了3个具体目标：1)研究insi和GREAT/LGR8在人类隐睾中的功能意义；2)探讨insi信号改变在小鼠和人类睾丸扭转中的作用；3)开展临床前小鼠研究，探讨insi作为治疗隐睾的药物疗法的作用。通过整合强大的发育生物学基础科学，利用基因工程小鼠模型和受影响的人类研究，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.