GUDMAP: Mapping molecular regionalization of cell types along the anterior-posterior axis of the urethra

GUDMAP：沿尿道前后轴绘制细胞类型的分子区域化

• 批准号: 9923343
• 负责人: MARTIN J COHN
• 金额: $ 11.2万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9923343
• 关键词: 3-Dimensional; Adult; Anatomy; Anterior; Atlases; Bartholin Glands; Bladder; Bulbourethral gland structure; Cells; Clitoris; Code; Columnar Epithelium; Communities; Congenital Abnormality; Data; Development; Disease; Distal; Epispadias; Epithelial; Excretory function; Female; Foundations; Gastrointestinal tract structure; Gene Expression; Gene Expression Profile; Genetic Transcription; Gland; Goals; Heterogeneity; Homeobox Genes; Human; Hypospadias; Immune response; Immunologics; In Situ Hybridization; Investigation; Knowledge; Lasers; Limb structure; Lower urinary tract; Male urethral structure; Mammals; Maps; Membranous Urethra; Molecular; Mus; Muscle; Neural tube; Optics; Organ; Pathway interactions; Pattern; Physiological; Polyps; Positioning Attribute; Process; Prostate; Prostatic; Prostatic Urethra; Research; Sexually Transmitted Diseases; Specific qualifier value; Sphincter; Structural defect; Structure; System; Therapeutic; Tissue Differentiation; Tissues; Transitional Epithelium; Tube; Urethra; Urinary tract infection; Urine; Urogenital Sinus; Urology; Urothelium; Utricle structure; Vagina; Vertebral column; body system; cell type; combinatorial; comparative; fly; human female; insight; laser capture microdissection; male; malformation; pathogen; penis; regional difference; sex; spine bone structure; tomography; transcription factor; transcriptome sequencing; urinary bladder neck

Project Summary In mammals, the urethra is the sole pathway for excretion of urine from the body and it is the primary point of entry for lower urinary tract infections and sexually transmitted diseases. Urethral malformations are among the most common birth defects in humans, yet our understanding of the molecular development of the urethra lags years, perhaps decades, behind other systems, such as the CNS, gut, and limbs. The anterior to posterior (A-P) axis of the urethra extends from the bladder to the urethral meatus, which opens at the tip of the penis in males or between the vaginal opening and the clitoris in females. At the cell and tissue levels, the urethral tube shows extensive heterogeneity along its A-P axis. Epithelial structure varies along this axis, with the linings of the pre-prostatic, prostatic, membranous, and penile urethra each having a distinctive character. Moreover, morphogenetic processes occur at discrete A-P positions along the urogenital sinus. For example, the accessory sex glands, such as the prostate and bulbourethral glands bud off the urogenital sinus at specific axial levels. Muscular sphincters also develop at highly localized regions. Despite this extensive anatomical regionalization, the molecular anatomy that establishes these patterns is not understood. In addition to this developmental significance, A-P identity of cells may influence adult function. Do male-female differences in cell type identity and molecular immunologic profiles along the A-P axis of the uretha influence colonization of the urethra and bladder by pathogens? Here we propose that specification of cell type identity along the urogenital sinus can be approached as a fundamental developmental problem of A-P regionalization. Analogous processes have been studied extensively in the gastrointestinal tract, resulting in a detailed picture of gut regionalization, sphincter development, specification of the positions and identities of organs, and control of cell type identities within those organs. Building on our GUDMAP2 project, which focused on the dorsoventral (D-V) axis of the LUT, this study aims to identify and map the molecular regionalization of cells along the A-P axis of the mouse and human urethra, from the bladder to the urethral meatus. We will use laser capture microdissection to isolate urethral cells from the pre-prostatic, prostatic, membranous, and penile regions of mouse and human urethra and use RNAseq to identify their transcriptional profiles. We will then carry out a comparative in situ hybridization analysis of mouse and human urethrae in sections and whole mounts, and we will use Optical Projection Tomography to map A-P patterns of gene expression in 3D. Our goal is to generate the foundation of gene expression data necessary for the urology research community to study how cell type identity along the urethra relates to development of congenital defects and to disease.

项目总结