Decidual Fibroblast Differntiation and Human Implantation

蜕膜成纤维细胞分化和人体植入

• 批准号: 7315916
• 负责人: LINDA C GIUDICE
• 金额: $ 31.86万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7315916
• 关键词: Affect; Angiogenic Factor; Apoptosis; Blood Vessels; CXCL1 gene; CXCL2 gene; Cell physiology; Cells; Characteristics; Clinical; Complex; Core Facility; Decidua; Decidual Cell Reactions; Development; Disease; Down-Regulation; Embryo; Embryonic Development; Endometrial; Endometrial Stromal Cell; Endometrium; Epithelial; Epithelium; Estradiol; FOXO1A gene; Fertilization; Fetal Growth Retardation; Fibroblasts; Gene Expression; Genes; Genetic; Germ Cells; Growth; Gynecologic; Human; Human Development; Immune; Immune response; Infertility; Insulin-Like Growth Factor II; Interleukin-8B Receptor; Invaded; Laboratories; Lead; Molecular; Outcome; PI3K/AKT; Pathway interactions; Phenotype; Placentation; Play; Pre-Eclampsia; Pregnancy Outcome; Pregnancy loss; Preparation; Process; Progesterone; Research Personnel; Resistance; Risk; Role; Signal Pathway; Signal Transduction; Somatomedins; Spontaneous abortion; Staging; System; Testing; Therapeutic; Transcriptional Activation; Up-Regulation; Woman; base; cell growth; chemokine; endometriosis; hormone regulation; implantation; in vitro Model; in vivo; natural Blastocyst Implantation; novel diagnostics; paracrine; pregnancy disorder; receptor; research study; response; steroid hormone; transcription factor; trophoblast

Implantation is an important part of early human develoment, because abnormalities in this process can lead to miscarriage, infertility, and pregnancy disorders, including fetal growth restriction and pre-eclampsia. Successful implantation requires estradiol (E2)-induced endometrial cellular growth and progesterone (P)- induced differentiation (decidualization). IGF-II is a major cytoytophoblast (CTB) product that regulates maternal decidual modulators of CTB invasion. We have recently found that IGF-II and other CTB products also elicit an immune phenotype in decidual fibroblasts that is dependent on the extent of P action on these cells. For example, the chemokine and angiogenic factor CXCL1 (GRO1) is up-regulated in response to IGF-II action on decidualized (but not non-decidualized) stromal fibroblasts. Its cognate receptor, CXCL2, is abundantly expressed in CTB, suggesting an important role for CXCL1/CXCL2 pair in maternal-trophoblast interactions. Limited P response in endometrium is a characteristic of women with endometriosis, a gynecologic disorder associated with infertility and poor pregnancy outcome, believed to be due, in large part, to P-resistance in the endometrium. We hypothesize that incomplete P action on endometrial stromal fibroblasts compromises their paracrine immune response to invading CTBs and may predispose women with this disorder to infertility and poor pregnancy outcome. Our specific aims are: Aim 1. To elucidate mechanisms underlying P-resistance in endometrial stromal fibroblasts from women with endometriosis, with a focus on P-regulated genes and FOXO1 A, a key determinant of stromal fibroblast cell fate. Aim 2. To elucidate decidua-trophoblast interactions and IGF-II signaling pathways in the immune response of endometrial stromal fibroblasts in women with and without endometriosis. Aim 3. To determine whether CXCL1, produced by the decidualized .stromal fibroblast in response to the invading trophoblast, affects human trophoblast proliferation, differentiation/invasion and acquisition of a vascular phenotype. Successful completion of the proposed experiments promises to strengthen our understanding of endometrial-based infertility and poor pregnancy outcomes in women with endometriosis and to contribute to the development of novel diagnostics and therapeutics associated with this disorder. Our participation in this Center is greatly enriched by our interactions with all investigators and access to its valuable core facilities.

植入是早期人类发展的重要组成部分，因为此过程中的异常可以 导致流产，不育和妊娠障碍，包括胎儿生长限制和先兆子痫。 成功的植入需要雌二醇（E2）诱导的子宫内膜细胞生长和孕酮（P） - 诱导的分化（deidualizatization）。 IGF-II是调节的主要细胞毒细胞（CTB）产品 CTB入侵的母体判决器。我们最近发现IGF-II和其他CTB产品 还引起决定性成纤维细胞中的免疫表型，取决于P作用的程度 细胞。例如，趋化因子和血管生成因子CXCL1（GRO1）响应于 IGF-II对de骨（但非非角化）基质成纤维细胞的作用。它的同源受体CXCL2是 在CTB中大量表达，这表明CXCL1/CXCL2对在母体 - 细胞细胞中的重要作用 互动。子宫内膜中的P反应有限是子宫内膜异位女性的特征 与不育和妊娠结局不佳相关的妇科疾病，被认为是造成的 一部分，在子宫内膜中抗性。我们假设对子宫内膜基质的不完全P作用 成纤维细胞损害其对入侵CTB的旁分泌免疫反应，并且可能使女性容易 这种疾病是不孕症和妊娠不良结果。我们的具体目的是：目标1。阐明 来自子宫内膜异位症女性的子宫内膜基质成纤维细胞中P-抗性的机制 侧重于P调节基因和FOXO1 A，这是基质成纤维细胞命运的关键决定因素。目标2 在免疫反应中阐明DecIDUA-TROPOPHAST相互作用和IGF-II信号通路 患有或没有子宫内膜异位的妇女的子宫内膜基质成纤维细胞。目标3。确定是否 CXCL1是由针对入侵的滋养细胞产生的。 人类滋养细胞增殖，分化/侵袭和血管表型的获取。成功的 提出的实验的完成有望加强我们对基于子宫内膜的理解 子宫内膜异位症女性的不孕症和妊娠结局不良，并为发展做出贡献 与这种疾病相关的新型诊断和治疗剂。我们参与这个中心是极大的 我们与所有调查人员的互动以及获得其宝贵核心设施的互动丰富。