Signaling mechanisms that modulate uterine 3D structure for pregnancy success

调节子宫 3D 结构以实现妊娠成功的信号机制

• 批准号: 10688107
• 负责人: Ripla Arora
• 金额: $ 41.95万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10688107
• 关键词: 3-Dimensional; Affect; Animals; Biological; Clinical; Computing Methodologies; Conceptions; Defect; Development; Embryo; Endometrial; Endometrium; Environment; Epithelium; Estrogens; Fetal Growth; Fetal Growth Retardation; Genetic; Goals; Health; Hormonal; Hormones; Human; Image Analysis; Inner Cell Mass; Knowledge; Location; Luteal Phase; Mammalian Oviducts; Menstrual cycle; Methods; Modeling; Molecular; Mus; Mutant Strains Mice; Organ; Outcome; Ovarian Hyperstimulation Syndrome; Ovarian hormone; Pathologic; Pathway interactions; Patients; Pattern; Phase; Physiological; Placental Insufficiency; Play; Positioning Attribute; Pre-Eclampsia; Pregnancy; Pregnancy Outcome; Pregnancy loss; Premature Birth; Preparation; Progesterone; Reproductive Technology; Research; Role; Saline; Serum; Shapes; Signal Pathway; Signal Transduction; Source; Spontaneous abortion; Stimulus; Structure; Superovulation; Technology; Testing; Three-Dimensional Image; Time; Tissues; Uterus; Visualization; WNT5A gene; Woman; assisted reproduction; blastocyst; confocal imaging; early pregnancy; egg; fertility improvement; healthy pregnancy; human subject; implantation; improved; inhibitor; insight; mouse model; mutant; natural Blastocyst Implantation; novel; novel strategies; nutrient absorption; pregnant; public health relevance; receptor; subfertility; success; three dimensional structure; uterine receptivity

PROJECT SUMMARY/ABSTRACT Although much is known about the embryo during early development, the structural uterine environment in which the early embryo develops is not well understood. A poor uterine environment at the time of blastocyst entry and attachment can cause long lasting detrimental effects on the health of the growing embryo, leading to defects such as miscarriage, placental insufficiency, intra-uterine growth restriction, preeclampsia and preterm birth. Using confocal imaging in combination with 3D image analysis we have identified and quantified dynamic changes in murine uterine luminal structure in preparation for implantation. When applied to mouse mutants deficient in progesterone signaling, mice with excess progesterone signaling or mice deficient in WNT5A signaling, with known molecular implantation defects, this approach reveals striking abnormalities in uterine structure at the time of implantation. The goal of this proposal is to determine, embryo and progesterone driven mechanisms that guide uterine folding in preparation for embryo implantation and pregnancy success. In Aim 1 we will determine how the embryo itself affects the 3D structure of the uterus. Using a time-course we will determine the temporal pattern of fold formation along the mesometrial-anti mesometrial axis. We will determine if the embryo is required as a physical object or as a biological signaling center to cause structural changes in the uterine lumen. In Aim2 we will test the hypothesis that progesterone influences receptivity of the endometrium by shaping uterine 3D structure. First we will assess endometrial folding in human subjects in both the estrogen dominant proliferative and progesterone dominant secretory phase of the menstrual cycle. We will then use physiological, supra-physiological progesterone treatment, and a mouse model of superovulation with increased progesterone levels, to determine how progesterone regulates folding. We will also use mouse mutants deficient in progesterone signaling to determine if progesterone regulates folding developmentally or during early pregnancy. Studies in Aim 3 will determine if progesterone affects uterine luminal shape by interacting with the WNT5A signaling pathway. We will also test if aberrant localization of embryos and aberrant axis alignment, in aberrantly structured folds, explains the entirety of poor pregnancy outcomes in aberrant folding mutants (superovulated and mutants deficient in WNT5A signaling). The methods developed in this proposal will be crucial to analyze the uterine structure in three- dimensions for different implantation-defective genetic mutants, pathological conditions, and will help uncover novel molecular and structural pathways involved in successful implantation. The long-term vision of my research is to identify novel uterine 3D structure based mechanisms that govern endometrial receptivity with the goal of developing new approaches to improve fertility outcomes for assisted reproduction and potential clinical situations for patients with hormonal disruptions.

项目摘要/摘要 尽管对早期发育期间的胚胎知之甚少，但结构性子宫 早期胚胎发展的环境尚不清楚。当时的子宫环境不佳 胚泡的进入和依恋会对增长的健康造成持久的有害影响 胚胎，导致缺陷，例如流产，胎盘功能不全，内部生长限制， 子痫前期和早产。将共聚焦成像与3D图像分析结合使用，我们有 在准备植入的过程中，鉴定出和量化的动态变化。 当应用于孕酮信号不足的小鼠突变体时，孕激素信号过多的小鼠 或缺乏Wnt5a信号传导的小鼠，由于已知的分子植入缺陷，这种方法揭示了 植入时，子宫结构异常。 该提案的目的是确定，胚胎和孕激素驱动的机制 指导子宫折叠以准备胚胎植入和妊娠成功。在目标1中，我们将 确定胚胎本身如何影响子宫的3D结构。使用时间表，我们将确定 沿介质 - 抗中轴轴的折叠形成的时间模式。我们将确定是否 需要胚作为物理物体或生物信号中心，以引起结构性变化 子宫腔。在AIM2中，我们将测试孕酮会影响子宫内膜接受能力的假设 通过塑造子宫3D结构。首先，我们将评估人类受试者的子宫内膜折叠 月经周期的雌激素显性增生和孕酮主导阶段。我们将 然后使用生理上，生理学上的孕酮治疗，并使用小鼠超卵形模型 孕酮水平升高，以确定孕酮如何调节折叠。我们还将使用鼠标 孕酮信号缺乏的突变体以确定孕酮是否在发育中调节折叠或 在怀孕初期。 AIM 3中的研究将确定孕激素是否会通过 与WNT5A信号通路相互作用。我们还将测试胚胎的异常定位和 异常结构折叠中的异常轴对齐，解释了整个不良妊娠结局 异常的折叠突变体（超含水量和突变体缺乏Wnt5a信号传导）。 本提案中开发的方法对于分析三个子宫结构至关重要 不同植入缺陷遗传突变体，病理状况的维度，将有助于发现 成功植入的新型分子和结构途径。我的长期愿景 研究是确定基于子宫3D结构的新型基于子宫内膜接受性的机制 开发新方法以改善辅助生殖和潜力的生育能力结果的目标 激素干扰患者的临床情况。

项目成果

Murine uterine gland branching is necessary for gland function in implantation.

小鼠子宫腺分支对于着床时的腺体功能是必需的。

• DOI: 10.1101/2023.11.01.565233
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Granger,Katrina;Fitch,Sarah;Shen,May;Lloyd,Jarrett;Bhurke,Aishwarya;Hancock,Jonathan;Ye,Xiaoqin;Arora,Ripla
• 通讯作者: Arora,Ripla