Insulin-3 in Human Testicular Disease

人类睾丸疾病中的胰岛素 3

• 批准号: 6969441
• 负责人: LINDA A. BAKER
• 金额: $ 30.42万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-10 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6969441
• 关键词: biological signal transduction; biopsy; cell surface receptors; cryptorchidism; gene mutation; genetic screening; hormone regulation /control mechanism; hormone therapy; human subject; human tissue; in situ hybridization; insulin; laboratory mouse; longitudinal human study; nonhuman therapy evaluation; reproductive development; reproductive system disorder chemotherapy

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.

描述（由申请人提供）：睾丸异常体面的异常代表了小儿泌尿科中一些最常见的诊断。该赠款的总体目的是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25岁以下的4,000名男性中有1个是睾丸的自发旋转，这可能导致睾丸死亡。这可能是由于异常的睾丸发育。此外，隐脑术，睾丸缺乏阴囊，是影响出生时3％的雄性婴儿最常见的生殖器异常。鉴于隐齿术的发生率越来越多，与睾丸扭转和隐齿术有关的频繁发生以及对睾丸发育机制的更深入的理解已经出现了一个关键问题。最近鉴定出的睾丸激素LNSULIN-3（INSIS）及其最近鉴定的G蛋白偶联受体Great/LGR8对于正常的鼠睾丸下降至关重要。但是，这种荷尔蒙途径的作用尚未在人类中进行彻底研究。为了满足这一需求，提出了3个具体目的：1）研究人类隐式主义中Insis和Great/lgr8的功能意义； 2）探索改变INSIS信号传导作为小鼠和人类睾丸扭转的原因的作用； 3）进行临床前鼠研究，研究INSIS作为一种药物治疗cryptorchidism的作用。通过将强大的发展生物学基础科学与对受影响人类的研究的研究相结合，这项高度协作研究的总体目标是促进我们对控制睾丸发育的荷尔蒙途径的了解。