Signaling during mammalian urogenital-anorectal develop

哺乳动物泌尿生殖-肛门直肠发育过程中的信号传导

• 批准号: 6801002
• 负责人: LINDA A. BAKER
• 金额: $ 37.05万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-25 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6801002
• 关键词: androgen inhibitor; anorectal disorder; apoptosis; biological signal transduction; cell cell interaction; cell proliferation; clinical research; congenital disorders; cytoskeleton; developmental genetics; embryo /fetus toxicology; ephrins; gene mutation; genetic disorder; hormone regulation /control mechanism; human subject; laboratory mouse; protein tyrosine kinase; rectum /anus; reproductive development; reproductive system; reproductive system disorder; testosterone; urinary tract; urinary tract disorder

Malformations of urogenital-anorectal structures during embryonic development are frequently observed birth defects in humans. For instance, hypospadias, which is due to a failure of the urethral epithelial cells to tubularize, occurs in approximately 1 out of every 320 male births. The genes, proteins, and cell signaling networks that control development of urogenital and anorectal structures are poorly understood. The Eph family of receptor tyrosine kinases and their membrane- anchored ephrin ligands are highly conserved molecules that function in diverse cell-cell recognition events, including those required for axon pathfinding in the nervous system, in migration of neural crest cells and in vascular organization. Preliminary data is provided that show gene-targeted mice mutant for certain Eph receptors and ephrins display hypospadias and delayed septation of the cloaca and cloacal membrane, two common failures in midline fusion characteristic of abnormal urogenital-anorectal development. To explore these preliminary findings in greater detail, three specific aims are proposed: 1) To fully characterize the abnormal urogenital-anorectal development observed in the Eph and ephrin mutant mice; 2) To study and perturb the activities of Eph/ephrin signals in the urogenital system by developing in vitro and in vivo assays; and 3) To delineate the importance of Eph receptors and ephrins in human urogenital-anorectal development by documenting the expression of these molecules and by screening for mutations in ephrin genes in individuals born with hypospadias and other hindgut abnormalities. By combining the powers of mouse molecular genetics, biochemical analysis and clinical-based studies, the overall goal of this collaborative research project is to characterize in detail the cell-cell signal transduction events that are utilized in mammalian urogenital-anorectal development.

胚胎发育过程中泌尿生殖-肛门直肠结构的畸形是人类常见的出生缺陷。 例如，尿道下裂是由于尿道上皮细胞管状化失败造成的，大约每 320 名男性新生儿中就有 1 人患有尿道下裂。 人们对控制泌尿生殖系统和肛门直肠结构发育的基因、蛋白质和细胞信号网络知之甚少。 受体酪氨酸激酶的 Eph 家族及其膜锚定肝配蛋白配体是高度保守的分子，在多种细胞间识别事件中发挥作用，包括神经系统中轴突寻路、神经嵴细胞迁移和血管组织中所需的识别事件。 提供的初步数据显示，某些 Eph 受体和肝配蛋白的基因靶向小鼠突变体表现出尿道下裂以及泄殖腔和泄殖腔膜的延迟分隔，这是泌尿生殖-肛门直肠发育异常的中线融合特征的两种常见失败。 为了更详细地探索这些初步发现，提出了三个具体目标：1）充分表征在 Eph 和 ephrin 突变小鼠中观察到的异常泌尿生殖-肛门直肠发育； 2) 通过开发体外和体内试验来研究和干扰泌尿生殖系统中 Eph/ephrin 信号的活性； 3) 通过记录 Eph 受体和肝配蛋白在人类泌尿生殖-肛门直肠发育中的重要性，通过记录这些分子的表达并筛选患有尿道下裂和其他后肠异常的个体的肝配蛋白基因突变。 通过结合小鼠分子遗传学、生化分析和临床研究的力量，该合作研究项目的总体目标是详细描述哺乳动物泌尿生殖-肛门直肠发育中使用的细胞间信号转导事件。