Regulation of trophectoderm development by mevalonate pathway

甲羟戊酸途径调节滋养外胚层发育

• 批准号: 9386353
• 负责人: VERNADETH B ALARCON
• 金额: $ 7.7万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9386353
• 关键词: Adverse effects; Affect; Age; Awareness; Biological Preservation; Biology; Cell Differentiation process; Cell Line; Cells; Chemical Agents; Cholesterol; Congenital Abnormality; Data; Development; Embryo; Embryo Loss; Embryonic Development; Engineering; Environmental Risk Factor; Enzymes; Epidemiology; Female; Fertility; Fertilization; Fetal Death; Fetal Development; Foundations; Future; Goals; Hormonal Change; Human; Impairment; Inner Cell Mass; Lead; Link; Malignant Neoplasms; Microfilaments; Modeling; Molecular; Monomeric GTP-Binding Proteins; Mus; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Physiological; Placenta; Pregnancy; Production; Publications; Publishing; Regulation; Reporting; Research; Role; Series; Signal Transduction; Supplementation; System; Testing; Therapeutic; Uterus; Woman; base; blastocyst; body system; cell fate specification; cholesterol biosynthesis; environmental agent; epidemiology study; experimental study; fetal; geranylgeranyl pyrophosphate; geranylgeranylation; immortalized cell; implantation; in vivo; inhibitor/antagonist; innovation; insight; mevalonate; natural Blastocyst Implantation; novel; pregnant; preimplantation; reproductive; reproductive tract; rho GTP-Binding Proteins; tissue regeneration; toxicant

Proposal Abstract Fertility in women can be compromised by various environmental factors, including the medications they take, which may interfere with embryo development in the reproductive tract. Human epidemiological studies have been helpful to identify drugs that cause birth defects or fetal death. However, environmental insults on preimplantation stages, i.e., the first week of embryo development from fertilization to implantation, are nearly impossible to detect by epidemiology, because women become aware of being pregnant only after embryo implantation. If embryos are damaged by a toxic agent before implantation, women cannot even recognize they produced an embryo. To identify environmental insults that compromise embryos before implantation, we need to understand the molecular mechanisms behind preimplantation development, so that chemical agents that interfere with those mechanisms can be suspected as preimplantation toxicants. The proposed project investigates the role of the mevalonate pathway, the primary target of major cholesterol- lowering medications, in the first cell fate decision in preimplantation embryos. The project specifically focuses on how one of the end products of the mevalonate pathway, geranylgeranyl pyrophosphate, controls the activity of RHO small GTPase and HIPPO signaling to promote differentiation of the trophectoderm, i.e., the extraembryonic lineage responsible for implantation and placenta formation. The proposed studies should yield valuable information on how the crucial aspects of preimplantation development are regulated by the mevalonate pathway, and lay foundation for future research to determine the reproductive impact of cholesterol-lowering medications.

提案摘要 妇女的生育能力可能受到各种环境因素的影响，包括 他们服用的药物可能会干扰生殖道中的胚胎发育。 人类流行病学研究有助于确定导致出生缺陷或胎儿畸形的药物 死亡然而，在植入前阶段的环境损伤，即，胚胎第一周 从受精到着床，几乎不可能通过流行病学检测到， 因为女性只有在胚胎植入后才意识到自己怀孕了。如果胚胎 在植入前受到有毒物质的损害，妇女甚至不能意识到她们产生了一个 胚胎为了在植入前识别损害胚胎的环境损伤，我们需要 了解植入前发育背后的分子机制，以便化学试剂 干扰这些机制的物质可能被怀疑是植入前毒物。拟议 该项目调查了甲羟戊酸途径的作用，主要胆固醇的主要目标， 降低药物，在植入前胚胎的第一个细胞命运决定。项目 特别关注甲羟戊酸途径的最终产物之一， 焦磷酸盐，控制RHO小GT3和HIPPO信号传导的活性，以促进 滋养外胚层的分化，即，负责着床的胚外谱系， 胎盘形成拟议的研究应提供宝贵的信息，说明关键的 着床前发育的各个方面都受到甲羟戊酸途径的调节， 用于未来的研究，以确定降胆固醇药物对生殖的影响。