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Hamster: A Unique Model for Studying Implantation

仓鼠：研究植入的独特模型

基本信息

批准号：
7889072
负责人：
Bibhash Chandra Paria
金额：
$ 31.15万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-04-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7889072
关键词：
Address Adenovirus Vector Amphiregulin Animal Model Appearance Area Assisted Reproductive Technology Atrial Natriuretic Factor Binding Biological Brain Brain natriuretic peptide C-Type Natriuretic Peptide Cardiac Cavia Cell Differentiation process Cell surface Cells Clinical Conceptions Contraceptive methods DTR gene Decidual Cell Decidual Cell Reactions Defect Detection Development Diagnostic Disease Embryo Emotional Endometrium Epithelium Estrogens Event Exhibits Family Family member Family suidae Female Figs - dietary Gel Gene Expression Genes Goals Grant Guanylate Cyclase Hamsters Heart Atrium Histamine Homeostasis Hormonal Horns Human Immunohistochemistry Implant In Situ Hybridization In Vitro Individual Infertility Inflammatory LIF gene Ligands Mediating Messenger RNA Modeling Molecular Monkeys Morula Mucin-1 Staining Method Mus Muscle Muscle relaxants Natriuretic Peptides Oryctolagus cuniculus Ovarian PTGS2 gene Papio Pattern Physiological Population Pregnancy Pregnancy loss Prevention Process Progesterone Progress Reports Property Prostaglandins Rattus Receptor Gene Receptor Signaling Regulation Relaxation Research Reverse Transcriptase Polymerase Chain Reaction Role Sepharose Signal Transduction Signaling Molecule Site Smooth Muscle Source Specific qualifier value Spontaneous abortion Staging Stem cells Stress Stromal Cells Study models Subfecundity System Testing Therapeutic Time To specify Up-Regulation Uterine Contraction Uterus Vasodilation Woman Work aged atrial natriuretic factor receptor A autocrine base blastocyst cell type cytokine design enterotoxin receptor failure Implantation human embryonic stem cell implantation improved in vivo insight mRNA Expression member mouse model myometrium novel paracrine peptide hormone polypeptide C preference pregnant prevent public health relevance receptor reproductive social tool trophoblast uterine contractility uterine receptivity

项目摘要

DESCRIPTION (provided by applicant): Each species has developed its own strategy for implantation. Using a cross- species heterologous microarray we identified C-type natriuretic peptide (CNP) as a possible implantation signaling molecule in hamsters which exhibit progesterone- dependent implantation similar to rabbits, pigs, monkeys and most likely in humans. CNP is the third member of the natriuretic peptide (NP) family which also includes atrial- and brain-NPs (ANP and BNP). All NPs act via two types of guanylyl cyclase (GC) receptors, GC-A and GC-B. CNP has more preference for GC-B, while ANP and BNP prefer GC-A. Our preliminary results show that while CNP signaling predominates at the implantation site of hamsters, both ANP/BNP and CNP signalings are active at the implantation sites of both mice and hamsters. These observations together with uterine relaxation properties of CNP and ANP, trophoblast outgrowth by BNP, induction of implantation by BNP, and infertility in GC-B null females suggest that NP signaling strongly influences the implantation process. Thus, we formulated a working hypothesis that NP ligand-receptor signaling influences several biologically and clinically important aspects of implantation: 1) muscular tone of the receptive uterus, 2) blastocyst-uterine cross talk prior to implantation, 3) trophoblast attachment, outgrowth and invasion, and 4) uterine stromal cell decidualization. Therefore, our Specific Aims are to study in hamsters: 1) influence of the blastocyst on the uterus prior to and at the time of implantation; 2) functions of NPs in regulation of uterine contractility prior to and during the time of implantation; and 3) the role of NP ligand-receptor signaling in initiation of implantation and decidualization. We will use multiple experimental approaches including qPCR, Northern and in situ hybridization, immunohistochemistry, in vivo adenoviral vector-driven gene inhibition, in vitro uterine contraction studies, and others to accomplish our goals. Deciphering the regulatory events required for implantation will provide insight into the potential causes of defects in implantation and infertility in women. Thus, these studies in hamsters that show progesterone-dependent implantation may provide useful information in the development of diagnostic and therapeutic tools that can be used in detection, prevention and treatment of female reproductive disorders, and improved technologies for assisted reproduction and contraception. PUBLIC HEALTH RELEVANCE: This proposal will address the role of natriuretic peptide ligand-reeptor signaling in the regulation of early pregnancy events. Defects in the uterus can cause infertility and pregnancy loss in women. This research will provide deeper insight into the molecular mechanisms underlying establishment of uterine receptivity/implantation/decidualization, and help to design clinical therapies to identify, treat and prevent reproductive problems in women.

描述（由申请人提供）：每个物种都制定了自己的植入策略。使用跨物种异源微阵列，我们鉴定出C型利尿钠肽(CNP)作为仓鼠中可能的植入信号分子，其表现出类似于兔子、猪、猴子且最有可能在人类中的黄体酮依赖性植入。 CNP 是利尿钠肽 (NP) 家族的第三个成员，该家族还包括心房NP 和脑NP（ANP 和BNP）。所有 NP 通过两种类型的鸟苷酸环化酶 (GC) 受体 GC-A 和 GC-B 发挥作用。 CNP更偏好GC-B，而ANP和BNP更偏好GC-A。我们的初步结果表明，虽然 CNP 信号在仓鼠的植入部位占主导地位，但 ANP/BNP 和 CNP 信号在小鼠和仓鼠的植入部位均很活跃。这些观察结果与 CNP 和 ANP 的子宫松弛特性、BNP 的滋养层生长、BNP 的植入诱导以及 GC-B 无效女性的不孕症一起表明 NP 信号传导强烈影响着床过程。因此，我们提出了一个工作假设，即 NP 配体-受体信号传导影响植入的几个生物学和临床重要方面：1) 接受子宫的肌张力，2) 植入前囊胚-子宫的交互作用，3) 滋养层附着、生长和侵袭，以及 4) 子宫基质细胞蜕膜化。因此，我们的具体目标是在仓鼠中进行研究：1）囊胚在着床前和着床时对子宫的影响； 2) 纳米颗粒在植入前和植入期间调节子宫收缩力的功能； 3) NP 配体-受体信号传导在着床和蜕膜化启动中的作用。我们将使用多种实验方法，包括 qPCR、Northern 和原位杂交、免疫组织化学、体内腺病毒载体驱动的基因抑制、体外子宫收缩研究等来实现我们的目标。破译植入所需的监管事件将有助于深入了解植入缺陷和女性不孕的潜在原因。因此，这些在仓鼠中进行的研究表明黄体酮依赖性着床可能为开发可用于检测、预防和治疗女性生殖疾病的诊断和治疗工具以及改进辅助生殖和避孕技术提供有用的信息。公共健康相关性：该提案将讨论利尿钠肽配体-受体信号传导在早期妊娠事件调节中的作用。子宫缺陷会导致女性不孕和流产。这项研究将更深入地了解子宫容受性/着床/蜕膜化建立的分子机制，并有助于设计临床疗法来识别、治疗和预防女性生殖问题。