Decidual Fibroblast Differentiation and Human Implantation

蜕膜成纤维细胞分化与人体植入

• 批准号: 8248071
• 负责人: LINDA C GIUDICE
• 金额: $ 53.85万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8248071
• 关键词: Affect; Angiogenic Factor; Apoptosis; Biological; 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; IL8RB gene; 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; Up-Regulation; Woman; base; cell growth; chemokine; endometriosis; hormone regulation; implantation; in vitro Model; in vivo; natural Blastocyst Implantation; novel diagnostics; novel therapeutics; 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.

着床是人类早期发育的重要组成部分，因为这一过程中的异常可能导致胚胎发育异常。 导致流产、不孕和妊娠障碍，包括胎儿生长受限和先兆子痫。 成功的着床需要雌二醇（E2）诱导的子宫内膜细胞生长和孕酮（P）- 诱导分化（蜕膜化）。IGF-II是一种主要的CTB产物， CTB侵袭的母体蜕膜调节剂。我们最近发现IGF-II和其他CTB产品 也引起蜕膜成纤维细胞的免疫表型，这取决于P对这些细胞的作用程度。 细胞例如，趋化因子和血管生成因子CXCL 1（GRO 1）响应于 IGF-II对蜕膜化（而非非蜕膜化）基质成纤维细胞的作用。其同源受体CXCL 2， 在CTB中大量表达，表明CXCL 1/CXCL 2对在母体滋养细胞中的重要作用 交互.子宫内膜有限的P反应是子宫内膜异位症的一个特征， 与不孕症和不良妊娠结局相关的妇科疾病，被认为是由于，在很大程度上， 部分，子宫内膜中的P-抵抗。我们推测不完全P作用于子宫内膜间质 成纤维细胞损害其对入侵CTB的旁分泌免疫应答， 与不孕症和不良妊娠结局有关。我们的具体目标是：目标1。阐明 子宫内膜异位症妇女子宫内膜间质成纤维细胞P抵抗的潜在机制， 重点是P调节基因和FOXO 1 A，基质成纤维细胞命运的关键决定因素。目标二。到 阐明免疫应答中的蜕膜-滋养层相互作用和IGF-II信号通路， 子宫内膜间质成纤维细胞在子宫内膜异位症和非子宫内膜异位症妇女中的作用目标3.以确定是否 CXCL 1，由蜕膜化的基质成纤维细胞对入侵的滋养层细胞产生，影响 人滋养层增殖、分化/侵袭和血管表型获得。成功 完成拟议中的实验有望加强我们对基于神经网络的 不孕症和子宫内膜异位症妇女的不良妊娠结局，并有助于发展 与这种疾病相关的新的诊断和治疗方法。我们在这个中心的参与， 通过我们与所有调查人员的互动以及访问其宝贵的核心设施，丰富了我们的知识。