Regulation of endovascular trophoblast cell development and uterine spiral artery remodeling

血管内滋养层细胞发育和子宫螺旋动脉重塑的调节

• 批准号: 9769510
• 负责人: Kaela Margaret Varberg
• 金额: $ 6.53万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-01 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9769510
• 关键词: Adult; Affect; Animal Model; Automobile Driving; Bioinformatics; Biological Models; Biology; Blastocyst Transfer; Blood; Blood Vessels; Cardiovascular Diseases; Cell physiology; Cells; Complex; Conceptus; Critical Pathways; Cultured Cells; Data; Derivation procedure; Development; Disease; Down-Regulation; Early Diagnosis; Embryo Transfer; Ensure; Environment; Epithelial; Epithelium; Excision; Extracellular Matrix; Fetal Development; Fetal Growth Retardation; Fetus; First Pregnancy Trimester; Gene Expression; Genes; Health; Hemochorial Placental Development; Human; Hypoxia; Impairment; In Vitro; Investigation; Knock-out; Learning; Life; MME gene; Malignant Neoplasms; Maternal-Fetal Exchange; Mediating; Modeling; Molecular; Morbidity - disease rate; Mothers; Mus; Nutrient; Obesity; Oxygen; Pathway Analysis; Pathway interactions; Phenotype; Physiology; Placenta; Placentation; Population; Pre-Eclampsia; Predisposition; Pregnancy; Pregnancy Complications; Pregnancy loss; Premature Birth; Property; Rattus; Regulation; Reproductive Physiology; Research; Research Personnel; Resistance; Role; Signal Pathway; Signal Transduction; Site; Spiral Artery of the Endometrium; Structure; Subfamily lentivirinae; Techniques; Testing; Therapeutic Agents; Tissue Sample; Tissues; Transplantation; Uterus; Vascular blood supply; Vascular remodeling; arterial remodeling; base; blastocyst; clinically relevant; early onset; effective intervention; experimental study; fetal; follow-up; human tissue; in vitro Model; in vivo; insight; interest; knock-down; laser capture microdissection; lentiviral-mediated; mortality; mutant; nervous system disorder; novel; novel strategies; postnatal; pregnancy disorder; response; skills; small hairpin RNA; stem cells; success; training opportunity; transcriptome; transcriptome sequencing; trophoblast

Project Summary / Abstract The oxygen and nutrient demands of a developing fetus increase as gestation progresses. Thus, the vessels, or spiral arteries, that facilitate the transfer of maternal blood to the conceptus must undergo extensive remodeling to ensure sufficient nutrient delivery and successful pregnancy. If vascular remodeling is insufficient and proper blood transfer cannot occur, pregnancy disorders such as preeclampsia, preterm birth, and intrauterine growth restriction can develop and threaten the health of both mother and fetus. Arterial remodeling is complex, as several maternal and extraembryonic cells interact at the maternal interface to regulate the extracellular matrix remodeling, cell loss, and cell invasion necessary for successful placentation. Despite this complexity, one critical mechanism for spiral artery remodeling is invasion of trophoblast cells into the maternal compartment. Previous studies from our lab indicate a critical function of matrix metalloproteinase 12 (MMP12) in regulating trophoblast invasion. However, little is known about the molecular mechanisms of MMP12-mediated trophoblast function. This lack of understanding can be attributed to several factors including difficulties in studying human physiology and interrogating cell populations of interest from tissues ex vivo. Therefore, the studies outlined in this proposal integrate animal models, human tissue samples, and novel approaches to identify critical mechanisms regulating trophoblast invasion and thus, spiral artery remodeling in placentation. Similar to humans, the rat possesses hemochorial placentation with deep trophoblast cell invasion and trophoblast-mediated spiral artery remodeling. Therefore, rat models will be used to determine how MMP12 regulates trophoblast cell function, and trophoblast cells will be isolated from rat placenta as well as first trimester human tissues to identify conserved mechanisms of endovascular trophoblast function. Lentiviral manipulation of blastocysts and embryo transfer will provide a unique opportunity to dissect the molecular mechanisms driving trophoblast invasion. Laser capture microdissection will enable derivation of discrete cell populations from both rat and human placental tissue. Overall, trophoblast invasion is critical to spiral artery remodeling and placentation. Further investigation into mechanisms regulating placental vascular remodeling during pregnancy will aid preventative efforts to detect pregnancy disorders at earlier onset and to develop safe and effective interventions.

项目总结/摘要 随着妊娠的进行，发育中的胎儿对氧气和营养的需求也会增加。因此，船只， 或螺旋动脉，促进母体血液转移到胎儿必须经历广泛的 重塑以确保充足的营养输送和成功怀孕。如果血管重塑 不能发生不充分和适当的血液转移，妊娠障碍如先兆子痫，早产， 胎儿宫内生长受限可发展并威胁母儿健康。动脉 重塑是复杂的，因为一些母体和胚外细胞在母体界面相互作用， 调节成功胎盘形成所必需的细胞外基质重塑、细胞损失和细胞侵入。 尽管这种复杂性，螺旋动脉重塑的一个关键机制是滋养层细胞侵入 母亲的隔间我们实验室以前的研究表明基质金属蛋白酶的一个关键功能 12（MMP 12）在调节滋养细胞侵袭中的作用。然而，关于其分子机制知之甚少。 MMP 12介导的滋养层功能。这种缺乏了解可归因于几个因素 包括研究人体生理学和从组织中询问感兴趣的细胞群的困难， vivo.因此，本提案中概述的研究整合了动物模型，人体组织样本， 新的方法，以确定关键机制调节滋养层入侵，因此，螺旋动脉 胎座形成中的重塑。与人类相似，大鼠具有血绒膜胎盘， 滋养层细胞侵袭和滋养层介导的螺旋动脉重塑。因此，将使用大鼠模型 为了确定MMP 12如何调节滋养层细胞功能，将从大鼠中分离滋养层细胞， 胎盘以及妊娠早期人体组织，以确定血管内 滋养层功能囊胚的慢病毒操作和胚胎移植将提供独特的 有机会剖析驱动滋养层入侵的分子机制。激光捕获显微切割 将能够从大鼠和人胎盘组织中获得离散的细胞群。总的来说，滋养层 侵袭对螺旋动脉重塑和胎盘形成至关重要。进一步调查机制 在怀孕期间调节胎盘血管重塑将有助于检测怀孕的预防性努力 因此，我们需要采取措施，预防和治疗早期发病的疾病，并制定安全有效的干预措施。