Human Trophoblast Differentiation and Notch Signaling

人类滋养层分化和Notch信号传导

• 批准号: 7633410
• 负责人: SUSAN J. FISHER
• 金额: $ 6万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7633410
• 关键词: Adhesives; Appendix; Arteries; Biological Markers; Birth; Blood Circulation; Blood Vessels; Blood flow; Cell Adhesion Molecules; Cell Communication; Cell Differentiation process; Cell Line; Cells; Complex; Data; Decidua; Development; Developmental Process; Disease; Embryo; Endothelial Cells; Endothelium; Eph Family Receptors; EphA1 Receptor; Ephrins; Epithelial; Family member; Figs - dietary; Gastrointestinal tract structure; Goals; Human; In Situ; Infertility; Invaded; Invasive; L-Selectin; Leukocytes; Ligands; Mammals; Maternal-Fetal Exchange; Modeling; Molecular; Neuropilins; Numbers; Organ; Pathway interactions; Pattern; Phenocopy; Placenta; Placentation; Play; Pregnancy; Pregnancy Outcome; Process; Production; Program Reviews; Property; Research Personnel; Respiratory physiology; Role; Side; Signal Transduction; Specialized Epithelial Cell; Structure; Structure of uterine vein; Testing; Thinking; Urinary system; Vascular Endothelial Growth Factors; Venous; Work; arteriole; base; cell type; cytotrophoblast; in utero; inhibitor/antagonist; insight; interest; interstitial; jagged1 protein; myometrium; notch protein; progenitor; programs; receptor expression; research study; theories; tissue culture; trophoblast

In eutherian mammals, the placenta is the first functional organ. Our previous work highlights the unusual plasticity of the human organ's specialized epithelial cells¿cytotrophoblasts (CTBs). For example, they mimic many aspects of endothelial cells (ECs) including their adhesion molecule repertoire and production of VEGF and Ang family members. Recently, we considered the possibility that CTB differentiation might involve mechanisms that regulate not only blood vessel (BV) formation, but more precisely arterial specification. The cell-cell interactions that occur as CTBs invade the uterine wall support this theory. CTBs breach the uterine BVs, thereby diverting maternal blood flow to the placenta. Subsequently, the cells form superficial connections with uterine veins. In contrast, they replace the EC lining of uterine spiral arterioles and intercalate within their muscular walls, a process that involves nearly the entire intrauterine course of these vessels. Thus, CTBs have the molecular machinery to preferentially colonize arteries. At a molecular level CTB progenitors within the placenta express EphB4, which is involved in venous specification. As the cells differentiate/invade they abruptly downregulate expression of this receptor and upregulate ephrinB2 required for arterial development. Accordingly, we examined CTB expression of Notch family members that play upstream regulatory roles in vascular development and arterial EC differentiation. We found that CTBs express a broad repertoire of these molecules and that inhibitors of Notch signaling impaired their invasion and ephrinB2 expression. Thus, we now propose experiments to test the hypothesis that Notch signaling plays a critical role in controlling CTB differentiation/invasion and the cells' ability to form a functional arterial endothelium. Accordingly, the goal of Aim 1 is to perform a detailed analysis of CTB expression of Notch family members. In Aim 2, we will study the functions of molecules that are expressed in a manner that suggests important roles. Thus, at the conclusion of the proposed experiments we will know a great deal more about the unusual process of CTB transformation into EC-like cells, which we think will yield important new insights into mechanisms that are crucial to normal placentation and may be dysregulated in cases of infertility or poor pregnancy outcome. By collaborating with other investigators in this U-54 program, we expect to gain additional insights into these normal and disease processes in terms of trophoblast function.

在Eutherian哺乳动物中，Pleceta是第一个功能器官。我们以前的工作突出了不寻常的 人体器官专业上皮细胞的可塑性。细胞增生细胞（CTB）。例如，他们 模仿内皮细胞（EC）的许多方面，包括它们的粘附分子库和产生 VEGF和ANG家庭成员。最近，我们考虑了CTB分化可能的可能性 涉及调节血管（BV）形成的机制，而且更精确的动脉 规格。当CTBS侵入子宫壁时，发生的细胞细胞相互作用支持了这一理论。 CTBS 违反子宫BV，从而将物物血流转移到斑点。随后，细胞形成 与子宫静脉的表面连接。相比之下，它们取代了子宫螺旋小动脉的EC衬里 并在其肌肉壁中进行插入 这些船只。这是CTB具有分子机械，优先定居动脉。在分子 Pleceta Express EPHB4中的CTB级祖细胞，涉及静脉规范。作为 细胞区分/入侵它们突然下调了该接收器的表达并上调ephrinb2 动脉发育所必需的。根据我们每个人都检查了Notch家族成员的CTB表达 在血管发育和动脉EC分化中发挥上游调节作用。我们发现CTB 表达这些分子的广泛曲目，并表达缺口信号的抑制剂损害其侵袭 和ephrinb2表达。这就是我们现在提出的实验来检验Notch信号的假设 在控制CTB分化/侵袭和形成功能动脉的能力中起着至关重要的作用 内皮。根据目标1的目标是对Notch的CTB表达进行详细分析 家庭成员。在AIM 2中，我们将以表达的方式研究分子的功能 提出重要角色。在提议的实验结束时，我们将知道很多 有关CTB转化为EC样细胞的异常过程的更多信息，我们认为这将产生重要 对对正常位置至关重要的机制的新见解，并且在 不育或怀孕不良。通过与此U-54计划中的其他调查员合作，我们 希望从滋养细胞功能方面获得对这些正常和疾病过程的更多见解。