The Mechanism of Cryptorchidism in LH Receptor Knockout Animals
LH受体敲除动物隐睾发生机制
基本信息
- 批准号:7353436
- 负责人:
- 金额:$ 29.3万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2008
- 资助国家:美国
- 起止时间:2008-04-01 至 2013-03-31
- 项目状态:已结题
- 来源:
- 关键词:AdultAgeAndrogen ReceptorAndrogensAnimalsApplications GrantsBilateralBlood CirculationCell ProliferationCell divisionCellsCongenital AbnormalityCryptorchidismDefectDevelopmentDisruptionEstradiolEstrogensExhibitsG-Protein-Coupled ReceptorsGene ExpressionGene TargetingGenesHistologyHumanIn VitroIncidenceInsulinLH ReceptorsLeucine-Rich RepeatMediatingMesenchymalMessenger RNAMolecularMusMuscle CellsMutant Strains MiceNerveNotch Signaling PathwayNumbersOrgan Culture TechniquesPathway interactionsPeptidesPhasePhenotypePlayProcessRecoveryRelaxinRoleScrotumSerumSiblingsSignal PathwaySignal TransductionStagingSystemTestisTestosteronecremaster muscleinsightknockout animalleydig interstitial cellmalemorphometrymyogenesisnotch proteinpostnatalpreventtestosterone replacement therapy
项目摘要
DESCRIPTION (provided by applicant): Cryptorchidism is by far the most common defect of sexual differentiation in humans. Testicular descent can be anatomically divided into two stages, i.e., transabdominal and inguinoscrotal phases. It is known that both insulin-like peptide 3 (INSL3) and androgen signaling pathways play critical roles in the control of the transabdominal phase of testis descent. However, the mechanism that regulates the inguinoscrotal phase is not completely understood, even though the incidence of this defect is much more common clinically. Targeted disruption of luteinizing hormone receptor (LHRKO) in mouse impaired development of adult-type Leydig cells which resulted in a dramatic reduction of INSL3 and testosterone levels. Surprisingly, serum estradiol levels were significantly increased. LHRKO males exhibited a bilateral cryptorchid phenotype resulting from a defect in inguinoscrotal testis descent. Histology, morphometry, cell proliferation and differentiation analyses demonstrated the defect was due to a reduction in mesenchymal cell division and differentiation into cremaster muscle cells during the second stage of testis descent. The expression of several genes in the gubernaculum that are known to be involved in gubernacular development, such as Hoxa10, Hoxa11, Wt1, Dll1 and Desrt, were not altered in mutant mice, while Lgr8, Notch1 and Numb mRNA levels were drastically deceased as compared with age-matched wild type siblings. In contrast, the expressions of Esr1 (ER1) and Esr2 (ER2) were significantly elevated. Postnatal testosterone replacement therapy (TRT) completed testicular descent into the scrotum and concomitantly normalized estradiol concentrations in the circulation and Esr1, Esr2, Lgr8, Notch1 and Numb mRNA levels in the gubernaculum. Remedy of the defect by TRT was neither dependent on recovery of adult-type Leydig cells nor the genitofemoral nerve but required androgen receptor activity in the gubernaculum. Using organ culture of the gubernaculum in vitro, androgen alone did not significantly stimulate proliferation of gubernacular mesenchymal cells without activation of the leucine-rich repeat-containing G-protein coupled receptor 8 (LGR8) signaling pathway by addition of INSL3 or relaxin. Co-treatment of estrogen with androgen prevented androgen-induced Lgr8 expression. Cotreatment of INSL3 and androgen increased Notch1 but not Numb mRNA levels. Taking these results together, we hypothesize that induction of the Lgr8 gene expression by androgen and activation of LGR8 signal impinging on the Notch system to stimulate gubernacular cell proliferation, differentiation and myogenesis are the essential molecular pathways in the control of gubernacular development to facilitate inguinoscrotal testis descent. In addition to androgen deficiency, unbalanced androgen/estrogen signals also play a role in contributing to the cryptorchid phenotype in LHR null animals. In this grant application, we propose four specific aims to verify our hypotheses: (1) to define the underlying mechanism by which androgen modulates the Lgr8 gene expression in the gubernaculum; (2) to assess the role of the LGR8 signaling pathway in androgen-induced inguinoscrotal testis descent in LHR null males; (3) to determine the importance of the Notch signaling pathway in mediating androgen and LGR8 signals to regulate gubernaculum development during inguinoscrotal testis descent and (4) to investigate the effect of estrogen on androgen-induced inguinoscrotal testis descent in LHR null males. Cryptorchidism is by far the most common birth defect in males. Although inguinoscrotal testis descent is known to be androgen dependent, the underlying mechanism remains unclear. The current proposal is focusing on determining androgen downstream target genes and subsequent signaling network during the process of inguinoscrotal testis descent, which may provide new insight into the causes of testis maldescent.
描述(由申请人提供):隐睾症是迄今为止人类最常见的性别分化缺陷。睾丸下降在解剖学上可分为两个阶段,即,经腹和腹股沟阴囊阶段。众所周知,胰岛素样肽3(INSL 3)和雄激素信号通路在睾丸下降的经腹阶段的控制中起着关键作用。然而,调节腹股沟阴囊期的机制尚未完全了解,即使这种缺陷的发生率在临床上更为常见。在小鼠中靶向破坏促黄体生成激素受体(LHRKO)会损害成年型Leydig细胞的发育,导致INSL 3和睾酮水平急剧降低。令人惊讶的是,血清雌二醇水平显着增加。LHRKO雄性动物表现出双侧隐睾表型,这是由于腹股沟阴囊睾丸下降缺陷所致。组织学、形态计量学、细胞增殖和分化分析表明,该缺陷是由于睾丸下降第二阶段间充质细胞分裂和向提睾肌细胞分化减少所致。已知参与引带发育的引带中几个基因的表达,如Hoxa 10,Hoxa 11,Wt 1,Dll 1和Desrt,在突变小鼠中没有改变,而Lgr 8,Notch 1和Numb mRNA水平与年龄匹配的野生型同胞相比急剧下降。相比之下,Esr 1(ER 1)和Esr 2(ER 2)的表达明显升高。出生后睾酮替代治疗(TRT)完成睾丸下降到阴囊,并伴随着正常的雌二醇浓度在循环和Esr 1,Esr 2,Lgr 8,Notch 1和Numb mRNA水平的引带。通过TRT补救缺陷既不依赖于成年型Leydig细胞的恢复,也不依赖于生殖股神经,但需要引带中的雄激素受体活性。在体外使用引带的器官培养物,单独的雄激素没有显著刺激引带间充质细胞的增殖,而没有通过添加INSL 3或松弛素激活富含亮氨酸重复序列的G蛋白偶联受体8(LGR 8)信号通路。雌激素与雄激素的共同治疗阻止了雄激素诱导的Lgr 8表达。INSL 3和雄激素共处理增加Notch 1但不增加Numb mRNA水平。综合这些结果,我们推测,雄激素诱导LGR 8基因表达和激活LGR 8信号冲击Notch系统,刺激引带细胞增殖,分化和肌生成是控制引带发育,促进腹股沟阴囊睾丸下降的重要分子途径。除了雄激素缺乏外,不平衡的雄激素/雌激素信号也在导致LHR缺失动物的隐睾表型中发挥作用。在本研究中,我们提出了四个具体的目标来验证我们的假设:(1)确定雄激素调节引带中LGR 8基因表达的潜在机制;(2)评估LGR 8信号通路在LHR缺失男性雄激素诱导的腹股沟阴囊睾丸下降中的作用;(3)确定Notch信号通路在介导雄激素和LGR 8信号以调节腹股沟阴囊睾丸下降过程中引带发育的重要性,以及(4)研究雌激素对雄激素的影响。在LHR缺失雄性中诱导腹股沟阴囊睾丸下降。隐睾症是迄今为止男性最常见的出生缺陷。虽然腹股沟阴囊睾丸下降已知是雄激素依赖性的,但其潜在机制仍不清楚。目前的研究重点是确定睾丸下降过程中雄激素下游的靶基因和随后的信号网络,这可能为睾丸发育不良的病因提供新的见解。
项目成果
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{{ truncateString('ZHENMIN LEI', 18)}}的其他基金
The Mechanism of Cryptorchidism in LH Receptor Knockout Animals
LH受体敲除动物隐睾发生机制
- 批准号:
7599022 - 财政年份:2008
- 资助金额:
$ 29.3万 - 项目类别:
The Mechanism of Cryptorchidism in LH Receptor Knockout Animals
LH受体敲除动物隐睾发生机制
- 批准号:
7798505 - 财政年份:2008
- 资助金额:
$ 29.3万 - 项目类别:
The Mechanism of Cryptorchidism in LH Receptor Knockout Animals
LH受体敲除动物隐睾发生机制
- 批准号:
8056551 - 财政年份:2008
- 资助金额:
$ 29.3万 - 项目类别:
The Mechanism of Cryptorchidism in LH Receptor Knockout Animals
LH受体敲除动物隐睾发生机制
- 批准号:
8245103 - 财政年份:2008
- 资助金额:
$ 29.3万 - 项目类别:
CONSEQUENCES OF MALE LH RECEPTOR GENE KNOCKOUT
男性 LH 受体基因敲除的后果
- 批准号:
6536309 - 财政年份:2001
- 资助金额:
$ 29.3万 - 项目类别:
CONSEQUENCES OF MALE LH RECEPTOR GENE KNOCKOUT
男性 LH 受体基因敲除的后果
- 批准号:
6317900 - 财政年份:2001
- 资助金额:
$ 29.3万 - 项目类别:
LH IN GNRH NEURONS DURING REPRODUCTIVE SENESCENCE
生殖衰老期间 GNRH 神经元中的 LH
- 批准号:
2859713 - 财政年份:1999
- 资助金额:
$ 29.3万 - 项目类别:
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