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ASPECTS OF BLASTOCYST IMPLANTATION

囊胚植入的各个方面

基本信息

批准号：
8097047
负责人：
Sudhansu K Dey
金额：
$ 10.87万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8097047
关键词：
Address Adhesions Animal Model Attenuated Basic Science Biology Birth Blastocyst Transfer Breast Cell Polarity Cell Proliferation Clinical Colon Carcinoma Complex Conceptions Contraceptive Agents Cytoskeleton Defect Development Down-Regulation E-Cadherin Embryo Transfer Endometrium Epithelial Epithelial Cells Epithelium Estrogens Event Family Female Female infertility Fertility Figs - dietary Functional disorder Gene Deletion Genes Goals Homeobox Homeobox Genes Human Human Biology Implant Investigation Knowledge Link Lung Luteal Phase Malignant neoplasm of ovary Mesenchymal Methylation Modeling Molecular Molecular Genetics Mus Ovarian Ovarian hormone Ovulation Pathway interactions Pattern Phase Phenotype Play Pregnancy Pregnancy Rate Pregnancy loss Progesterone Prostate Pseudopregnancy Publishing Readiness Refractory Regulation Reproduction Research Rest Role Science Scientist Screening procedure Signal Pathway Signal Transduction Simulate Site Specific qualifier value Spontaneous abortion Stimulus Stress Supplementation Testing Time Unwanted pregnancy Uterus Vagina Wild Type Mouse Woman base blastocyst cancer cell cancer therapy clinically relevant combat craniofacial cytokine editorial failure Implantation implantation improved innovation leukemia inhibitory factor male mouse model natural Blastocyst Implantation novel novel strategies overexpression pregnant preimplantation programs psychologic public health relevance research study small molecule tumor uterine receptivity

项目摘要

DESCRIPTION (provided by applicant): One prerequisite for mammalian reproduction is an effective reciprocal interaction between an implantation-competent blastocyst and the receptive uterus. The blastocyst will implant only when this molecular dialogue is established. The goal of this proposal is to better understand the mechanisms that direct uterine receptivity and nonreceptivity with the aim of improving female fertility. We will use conditionally gene-deleted mouse models to address the molecular basis of these events, since these models provide mechanistic information relevant to fertility in women. Human reproduction is complex and not very efficient. More than 30% of conceptions result in spontaneous abortion with most losses occurring around the time of implantation due to an inappropriate uterine milieu. Unwanted pregnancy loss causes psychological and economical stress to families, and is a challenging clinical problem. Based on our published and preliminary results, we hypothesize that homeobox-cytokine-Wnt signaling, involving Msx1, leukemia inhibitory factor (LIF) and Wnt5a, is critical for implantation. To address these questions, we will pursue the following specific aims in mice: (1) The first Specific Aim will test the hypothesis that Msx1 plays key roles in regulating various phases of uterine sensitivity to implantation by altering the luminal epithelial cell polarity and epithelial- mesenchymal interactions; (2) The second Specific Aim will test the hypothesis that Msx1 and LIF closely interact to direct various phases of uterine sensitivity; and (3) The third Specific Aim will test the hypothesis that overexpression of uterine Msx1 results in implantation failure, but extends the uterine preparedness to implantation. Our preliminary results with conditional deletion of uterine Msx1 and/or deletion of Lif hold great promise and have created a window of opportunity to generate molecular and genetic information on potential mechanisms by which the uterus becomes receptive or nonreceptive. This research is clinically relevant because Msx1 is downregulated in the human endometrium during the receptive phase (window of implantation).This simulates the situation in mice in which Msx1 is downregulated just prior to the initiation of implantation. The results derived from the proposed study using mouse models may help developing novel strategies to improve fertility in women.

描述（由申请人提供）：哺乳动物生殖的一个先决条件是有发育能力的囊胚和接受性子宫之间的有效相互作用。只有当这种分子对话建立时，胚泡才会植入。这项建议的目的是更好地了解机制，直接子宫容受性和非容受性的目的是提高女性生育能力。我们将使用条件性基因缺失小鼠模型来解决这些事件的分子基础，因为这些模型提供了与女性生育力相关的机制信息。人类的繁殖很复杂，而且效率不高。超过30%的受孕导致自然流产，大多数流产发生在着床前后，原因是子宫环境不当。意外流产给家庭造成心理和经济压力，是一个具有挑战性的临床问题。基于我们发表的和初步的结果，我们假设同源框-细胞因子-Wnt信号，涉及Msx 1，白血病抑制因子（LIF）和Wnt 5a，是植入的关键。为了解决这些问题，我们将在小鼠中追求以下具体目标：（1）第一个具体目标将测试Msx 1通过改变腔上皮细胞极性和上皮-间充质相互作用在调节子宫对植入的敏感性的各个阶段中起关键作用的假设;（2）第二个特异性目的将检验Msx 1和LIF密切相互作用以指导子宫敏感性的各个阶段的假设;（3）第三个特异性目的将检验子宫Msx 1过表达导致着床失败，但延长子宫准备着床的假设。我们的初步结果与子宫Msx 1和/或Lif的删除条件删除持有很大的希望，并创造了一个窗口的机会，以产生潜在的机制，子宫成为接受或非接受的分子和遗传信息。这项研究具有临床意义，因为Msx 1在人类子宫内膜的接受期（着床窗口期）下调，这模拟了小鼠在着床开始前Msx 1下调的情况。从使用小鼠模型的拟议研究中获得的结果可能有助于开发改善女性生育能力的新策略。