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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要 /摘要随着妊娠的进展，胎儿的氧气和养分需求增加。因此，船只，或螺旋动脉，有助于将母血转移到概念的情况重塑以确保足够的营养递送和成功的怀孕。如果血管重塑是无法发生不足和适当的血液转移，妊娠疾病，例如先兆子痫，早产，宫内生长限制可能会发展和威胁母亲和胎儿的健康。动脉重塑是复杂的，因为几个母体和胚外细胞在母体界面上相互作用调节成功胎盘所需的细胞外基质重塑，细胞损失和细胞侵袭。尽管这种复杂性，螺旋动脉重塑的一种关键机制是入侵滋养细胞孕产妇室。我们实验室的先前研究表明基质金属蛋白酶的关键功能 12（MMP12）调节滋养细胞入侵。但是，关于分子机制知之甚少 MMP12介导的滋养细胞功能。缺乏理解可以归因于几个因素包括研究人类生理学和从组织中询问感兴趣的细胞群的困难体内。因此，该提案中概述的研究整合了动物模型，人体组织样本和鉴定调节滋养细胞侵袭的关键机制的新方法，因此螺旋动脉胎盘重塑。与人类类似，大鼠具有深度的胎胎胎盘滋养细胞侵袭和滋养细胞介导的螺旋动脉重塑。因此，将使用大鼠模型确定MMP12如何调节滋养细胞的功能，将从大鼠中分离出滋养细胞细胞胎盘和先前的人类组织，以鉴定血管内的保守机制滋养细胞功能。胚胎和胚胎转移的慢病毒操纵将提供独特的剖析驱动滋养细胞侵袭的分子机制的机会。激光捕获微分解将使大鼠和人胎盘组织均可衍生离散的细胞群体。总体而言，滋养细胞入侵对于螺旋动脉的重塑和胎盘至关重要。进一步研究机制调节怀孕期间的胎盘血管重塑将有助于预防性努力检测怀孕早期发作并制定安全有效的干预措施。