Molecular and Cellular Regulation of Uterine Morphogenesis

子宫形态发生的分子和细胞调节

基本信息

批准号：
10750127
负责人：
Diana Machado
金额：
$ 3.57万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2024
资助国家：
美国
起止时间：
2024-02-03 至 2027-02-02
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10750127
关键词：
Advisory Committees Cell Death Cells Cellular Morphology Cervix Uteri Confocal Microscopy Data Development Disease Duct (organ) structure Ductal Epithelial Cell Ductal Epithelium Embryo Embryonic Development Epithelium Female Gene Expression Genes Genetic Models Genitourinary system Goals Gynecologic Human Development Image Immunofluorescence Immunologic Individual Infertility Knock-out Knockout Mice Knowledge Laboratories LacZ Genes Length Light Mammalian Oviducts Mammals Medical center Mesenchymal Mesenchyme Molecular Morphogenesis Mus Mutant Strains Mice Newborn Infant Organ Culture Techniques Play Positioning Attribute Postdoctoral Fellow Pregnancy Process Proliferating Publications Recording of previous events Reproductive Biology Reproductive Sciences Research Personnel Role Sexual Development Shapes Signal Transduction Spontaneous abortion Stains Structure of mesonephric duct Structure of paramesonephric duct System Texas Time Training Tube Urogenital Sinus Uterus Vagina Variant Visualization WNT7A gene Woman Work Writing cell behavior cell growth regulation developmental genetics deviant differential expression ex vivo imaging experimental study fetal healthy pregnancy mRNA Expression male mouse genetics mutant natural Blastocyst Implantation novel prevent programs reproductive development reproductive system disorder reproductive tract sperm cell symposium transcriptome transcriptomics whole genome

项目摘要

Project Summary In mammals, the uterus serves many functions including a passage for spermatozoa, embryo implantation, and fetal gestation. Congenital uterine anomalies are present in 25% of women with a history of miscarriage and infertility. It has been increasingly noted that uterine anomalies are simultaneously present with reproductive diseases. For this reason, it is necessary to further understand female reproductive development to better manage and prevent reproductive diseases in women. The female reproductive tract develops from a pair of epithelial tubes called the Müllerian ducts (MD). During embryonic development, the Müllerian ducts and adjacent mesenchyme differentiate into the oviducts, uterus, cervix, and upper part of the vagina. In many mammals, the MD must fuse at the midline for proper uterine morphogenesis. Formation of the uterus occurs with the differentiation, invagination, elongation, and fusion first, of the MD to the urogenital sinus (UGS) and secondly, the two MD fuse to each other at the body midline during uterine morphogenesis. Any divergence in MD fusion during human development can lead to uterine variation that may prevent a healthy pregnancy or delivery of a newborn. While there have been many studies on MD formation, it is currently unknown which genes and molecular mechanisms regulate the fusion of the MD ducts. Preliminary data from our lab shows that Wnt7a knockout mice have uterine abnormalities as a result of unfused MD, suggesting an essential role for Wnt7a in fusion of the two MD. Currently, the cellular behaviors and mechanisms that regulate MD fusion are poorly understood. The crosstalk between MD epithelium with the adjacent mesenchyme has not been studied in the context of MD fusion. In Aim 1, I will use ex vivo organ culture time-lapse imaging and immunofluorescence staining to determine which cellular changes coordinate MD fusion. In Aim 2, I will use spatial transcriptomics to identify differentially expressed genes downstream of Wnt7a, using wild-type and Wnt7a knockout embryos. The objective of this proposal is to determine the precise timing, position, and length of MD fusion, what cellular changes occur during MD fusion, and the downstream genes of Wnt7a that govern MD fusion for uterine morphogenesis. Our primary hypothesis is that Wnt7a directs the crosstalk between MD epithelium with the adjacent mesenchyme to instruct MD fusion to form a portion the uterus. The Behringer laboratory located at MD Anderson in the Texas Medical Center has expertise in reproductive biology, mammalian developmental genetics, and mouse genetic models. During my graduate training, I will meet with my Sponsor biweekly, advisory committee as a group biannually, and with experts on the subject individually as needed. I have written a chapter review and will write two first-author publications summarizing my findings. I will present my work at both my graduate program seminars and at two national conferences annually. Ultimately this work will facilitate my long-term goals of conducting my postdoctoral studies in reproductive sciences and becoming an independent reproductive biology researcher.

项目概要在哺乳动物中，子宫具有多种功能，包括精子通道、胚胎植入和 25% 有流产史的女性存在先天性子宫异常。人们越来越多地注意到子宫异常与生殖能力同时存在。为此，有必要进一步了解女性生殖发育情况，以便更好地防治疾病。管理和预防女性生殖系统疾病。上皮管称为苗勒管 (MD) 在胚胎发育过程中，苗勒管和在许多情况下，相邻的间质分化为输卵管、子宫、子宫颈和阴道上部。对于哺乳动物，MD 必须在中线融合，以实现子宫的正常形成。首先，MD 向泌尿生殖窦 (UGS) 分化、内陷、伸长和融合，其次，在子宫形态发生过程中，两个MD在身体中线处相互融合。人类发育过程中的 MD 融合可能导致子宫变异，从而可能妨碍健康妊娠或虽然对于 MD 的形成有很多研究，但目前尚不清楚是哪一种。我们实验室的初步数据显示，基因和分子机制调节 MD 导管的融合。 Wnt7a 基因敲除小鼠由于未融合的 MD 而出现子宫异常，这表明其具有重要作用对于两种MD融合中的Wnt7a，目前，调节MD融合的细胞行为和机制。对MD上皮与邻近间质之间的串扰还知之甚少。在 MD 融合的背景下进行研究在目标 1 中，我将使用离体器官培养延时成像和在目标 2 中，我将使用免疫荧光染色来确定哪些细胞变化可协调 MD 融合。使用野生型和空间转录组学来识别 Wnt7a 下游的差异表达基因该提案的目的是确定 Wnt7a 敲除胚胎的精确时间、位置和长度。 MD融合过程中发生了哪些细胞变化，以及控制Wnt7a的下游基因 MD 融合对子宫形态发生的影响我们的主要假设是 Wnt7a 指导两者之间的串扰。 MD上皮与邻近的间质促使MD融合形成子宫的一部分。位于德克萨斯医学中心 MD 安德森的贝林格实验室拥有生殖领域的专业知识在我的研究生培训期间，我将学习生物学、哺乳动物发育遗传学和小鼠遗传模型。每两周与我的赞助商会面一次，每两年与咨询委员会会面一次，并与该主题的专家会面一次我根据需要单独写了一篇章节评论，并将撰写两篇第一作者出版物进行总结。我将在研究生课程研讨会和两次全国会议上展示我的研究成果。最终，这项工作将促进我进行博士后研究的长期目标。生殖科学并成为一名独立的生殖生物学研究员。