The Role of Androgen in Sexual Differentiation of the Urethra

雄激素在尿道性别分化中的作用

• 批准号: 8869596
• 负责人: Christine E Larkins
• 金额: $ 12.01万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-20 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8869596
• 关键词: Affect; Androgen Receptor; Androgen-Insensitivity Syndrome; Androgens; Area; Attenuated; Congenital Abnormality; Congenital adrenal hyperplasia; Cues; Defect; Development; Developmental Endocrinology; Duct (organ) structure; Ejaculatory duct structure; Embryo; Environment; Epithelial; Epithelium; Female; Female urethral structure; Feminization; Genitourinary system; Gland; Gonadal structure; Histology; Hormonal; Hormones; Human; Hypospadias; Individual; Lateral; Lead; Lower urinary tract; Male urethral structure; Mesenchyme; Methods; Modeling; Mus; Organ; Phenotype; Phenotypic Sex; Play; Population; Positioning Attribute; Postdoctoral Fellow; Process; Production; Prostate; Proteomics; Reporter; Research; Research Personnel; Research Training; Resources; Role; Running; Sex Differentiation Disorders; Signal Transduction; Sinovaginal Bulb; Sinus; Site; Structure; Structure of mesonephric duct; Structure of paramesonephric duct; Tissues; Training; Urethra; Urogenital Sinus; Vagina; Work; base; career development; congenital anomaly; external genitalia; male; novel; prevent; public health relevance; response; sex; symposium; urinary bladder neck

 DESCRIPTION (provided by applicant): Disorders of sexual differentiation (DSDs) are congenital conditions in which the phenotypic sex of an individual is atypical, often resulting from defects in hormonal signaling. Sexual differentiation of the urogenital sinus, the embryonic precursor to the urethra, is required for development of the prostate and other associated glands in males and for development of the vagina in females. Little is known about how the embryonic male and female urethra respond to hormonal cues to undergo sexual differentiation. This proposal aims to examine sexual differentiation of a structure called the sinus ridge, a thickened portion of the urogenital sinus where the ejaculatory ducts attach in the male and the developing vagina attaches in the female. The urogenital sinus and sinus ridge are initially identical in both sexes until hormone production begins in the embryonic gonads. Under hormonal influence, the sinus ridge is maintained internally in the male, while in the female, the ridge elongates and shifts caudally along the urogenital sinus until it reaches the base of the external genitalia, separating from the urethra to allow formation of a vaginal opening. It is not clear how development and subsequent sexual differentiation of the sinus ridge occurs, but the development of this structure is often perturbed in DSDs. For example, in males with reduced androgen signaling, the sinus ridge inappropriately shifts caudally and can lead to formation of a vaginal opening in these males. In females exposed to excess androgen embryonically, the vagina remains attached to the urethra internally and must be corrected surgically. This proposal will aid in the understanding of the urogenital phenotypes that result from DSDs by identifying how the sinus ridge develops in male mouse embryos lacking androgen signaling and in female mouse embryos exposed to excess androgen (Aim 1). In addition, the tissue population that requires androgen signaling for sinus ridge sexual differentiation will be determined through conditional deletion of the androgen receptor (Aim 2). Finally, targets of androgen that are responsible for sexual differentiation of the sinus ridge will be determined through a novel proteomics analysis of the mouse sinus ridge tissue (Aim 3). Besides this project having importance in our understanding of DSDs, the proposed research will be instrumental in the training and career development of the candidate, Dr. Christine Larkins. The proposed training plan will allow her to branch into new areas of research including developmental endocrinology and quantitative proteomics, it will give her the resources to attend courses and conferences relevant to her research and training, and will allow her to transition from a postdoctoral fellow to an independent researcher running her own lab.

 描述（由申请人提供）：性分化障碍（DSD）是一种先天性疾病，其中个体的表型性别是非典型的，通常由激素信号传导缺陷引起。尿道的胚胎前体尿生殖窦的性别分化是男性前列腺和其他相关腺体发育以及女性阴道发育所必需的。关于胚胎期的男性和女性尿道如何对激素信号做出反应以进行性别分化，人们知之甚少。这项提议旨在研究一种称为窦脊的结构的性别分化，窦脊是尿生殖窦的增厚部分，男性射精管附着在这里，女性发育中的阴道附着在这里。尿生殖窦和窦脊最初在两性中是相同的，直到胚胎性腺开始产生激素。在激素的影响下，男性的窦嵴保持在内部，而女性的窦嵴延长并沿尿生殖窦向尾侧沿着，直到到达外生殖器的基部，与尿道分离，形成阴道口。目前尚不清楚窦嵴的发育和随后的性别分化是如何发生的，但这一结构的发育在DSD中经常受到干扰。例如，在雄激素信号传导减少的男性中，窦嵴不适当地向尾部移位，并可能导致这些男性中形成阴道开口。在胚胎期暴露于过量雄激素的女性中，阴道仍然附着在尿道内部，必须通过手术矫正。这一建议将有助于通过确定缺乏雄激素信号传导的雄性小鼠胚胎和暴露于过量雄激素的雌性小鼠胚胎中的窦嵴如何发育来了解DSD导致的泌尿生殖表型（目的1）。此外，将通过雄激素受体的条件性缺失来确定窦嵴性分化需要雄激素信号传导的组织群体（目的2）。最后，将通过对小鼠窦嵴组织进行新的蛋白质组学分析来确定负责窦嵴性别分化的雄激素靶点（目的3）。除了这个项目在我们对DSD的理解方面具有重要意义外，拟议的研究将有助于候选人克莉丝汀拉金斯博士的培训和职业发展。拟议的培训计划将使她能够分支到新的研究领域，包括发育内分泌学和定量蛋白质组学，这将使她有资源参加与她的研究和培训相关的课程和会议，并将使她能够从博士后研究员过渡到独立研究员，经营自己的实验室。