VEGF signaling in placental development and disease

胎盘发育和疾病中的 VEGF 信号传导

• 批准号: 10159946
• 负责人: Nihar R Nayak
• 金额: $ 32.87万
• 依托单位: UNIVERSITY OF MISSOURI KANSAS CITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10159946
• 关键词: Abruptio Placentae; Acute; Address; Affect; Blood flow; Cell Differentiation process; Cell physiology; Cells; Chorion; Clinical; Data; Decidua; Defect; Development; Diagnosis; Diagnostic; Discipline of obstetrics; Disease; Endothelial Growth Factors Receptor; Fetal health; Functional disorder; Gene Expression; Gene Expression Profiling; Giant Cells; Goals; Growth Factor Overexpression; Health; Health Care Costs; Heart; Hemorrhage; Heterogeneity; Human; Hypoxia; Intercellular Junctions; Knowledge; Lasers; Lead; Life; Location; Maternal Health; Mediating; Microdissection; Modality; Molecular; Mus; Pathogenesis; Pathologic; Pathology; Placenta; Placenta Diseases; Placentation; Play; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Prevention; Process; Production; Research; Risk; Role; Signal Pathway; Signal Transduction; Site; Spiral Artery of the Endometrium; Symptoms; System; Techniques; Therapeutic; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factors; Woman; Work; angiogenesis; base; disability; disorder subtype; experimental study; human model; implantation; improved; in vivo; insight; knock-down; nanoparticle; novel; novel diagnostics; novel therapeutics; precursor cell; pregnancy disorder; prevent; response; targeted treatment; treatment strategy; trophoblast; trophoblast stem cell

Every year over 300,000 women die from pregnancy complications, and over 6.5 million more suffer complications that result in life-long disability, for which $41 billion is spent on healthcare costs. However, little is known about the development and differentiation of the cells—extravillous trophoblasts (EVTs)—at the heart of most human pregnancy complications. Our overarching goal is to develop mechanism-based strategies to prevent, diagnose, and treat pregnancy complications associated with faulty trophoblast development. We have strong evidence that vascular endothelial growth factor (VEGF) acts directly on trophoblast stem cells and plays a key role in the differentiation of junctional zone cells and specific subtypes of trophoblast giant cells (TGCs) in mice, which are orthologous to EVTs in humans. We discovered that different levels of decidual VEGF overexpression at the implantation site stimulates placental production of the potent endogenous VEGF antagonist soluble fms-like tyrosine kinase 1 (sFlt1) and induces a spectrum of symptoms in mice similar to those of human obstetrical diseases, from preeclampsia to abruptio placentae. Our preliminary data show that specific symptoms of each of those diseases are associated with abnormal development of a subset of TGCs and junctional zone cells. Thus, we hypothesize that the level of VEGF overexpression during early placental development corresponds to abnormal development of specific subtypes of TGCs associated with distinct pregnancy complications and that the diseases associated with excess sFlt1 production can be treated by reducing sFlt1 only at later stages of pregnancy. We also hypothesize that different EVT subtypes exist and that excess VEGF can cause disproportionate expansion of specific EVT subtypes in humans. Thus, our experiments will define the role of VEGF in the development of specific trophoblast subtypes (Aim 1), how levels of VEGF affect these cells at each stage of placental development in vivo in the mouse, how these cellular defects are related to specific pregnancy outcomes (Aim 2), and where and when VEGF signaling pathways can be targeted for prevention and therapeutic strategies (Aim 2). Several novel techniques will be used to address these questions, including inducible placenta- and decidua-specific gene expression systems for precise control of gene expression at discrete stages of pregnancy, and nanoparticle-mediated delivery of morpholinos to specific cells in the placenta. Finally, our preliminary data suggest that analogous EVTs may be present at similar locations in the human placenta as TGCs in mice and that VEGF may play a similar role in human trophoblast differentiation. We will characterize the diversity of EVTs in human placenta using laser microdissection, global transcriptional profiling, and a culture model of human chorionic trophoblast progenitor cell differentiation (Aim 3). These studies will characterize the previously unappreciated relationship between excess VEGF signaling and faulty trophoblast differentiation and the resulting spectrum of pregnancy disorders and provide specific guidance for the development of diagnostics and targeted therapies for these disorders.

每年超过30万名妇女死于怀孕并发症，而650万以上 导致终身残疾的并发症，为此，410亿美元用于医疗保健费用。 关于细胞的发展和区分 - 室内滋养细胞（EVT） - 心脏已知 在大多数人的怀孕汇编中，我们的总体目标是制定基于机制的策略 我们预防，诊断和治疗与40个滋养细胞发展有关的汇编 有强有力的证据表明血管内皮生长因子（VEGF）直接作用于滋养细胞邮票细胞 并在连接区细胞的区分和滋养细胞巨人的特定亚型中起关键作用 小鼠中的细胞（TGC），与人类的EVT是直系同源的。 植入处的VEGF过表达模拟了胎盘生产术的内源性VEGF 拮抗剂可溶性FMS样酪氨酸激酶1（SFLT1），并在小鼠中诱导一系列症状。 从先兆子痫到破坏性胎盘的人类产科疾病。 每种疾病的特定症状都与TGC子集的异常发育有关 和连接区细胞。 开发对应于与不同的TGC的特定亚型的浸没 怀孕并发症以及与过量SFLT1产生相关的疾病可以治疗 仅在怀孕的后期减少SFLT1。 多余的VEGF导致人类特定EVT亚型的比例不成比例 实验将定义VEGF在特定奖杯亚型的发展中的作用（AIM 1），如何 VEGF的水平在小鼠体内胎盘发育的每个阶段都会影响这些细胞，围绕这些细胞 细胞缺陷与特定的妊娠结局有关（AIM 2） 可以将途径用于预防和治疗策略（AIM 2）。 用于解决这些问题，包含诱导型胎盘和Decidua特异性基因Express Systems 为了精确控制妊娠离散阶段的基因表达，纳米颗粒介导 胎盘中的特定细胞的形态学。 在人胎盘中的类似位置与小鼠中的TGC相似，而VEGF可能在 我们将使用激光表征人胎盘中EVT的多样性 微分解，全局转录分析和人绒毛膜滋养细胞祖细胞的培养模型 细胞分化（AIM 3）。 过多的VEGF信号传导和铸造滋养细胞的差异差异以及妊娠疾病的范围 并为开发诊断和针对TESE疾病的疗法提供具体的指导。

项目成果

Placenta-specific drug delivery by trophoblast-targeted nanoparticles in mice.

通过靶向滋养层的纳米颗粒在小鼠体内进行胎盘特异性药物输送

• DOI: 10.7150/thno.22904
• 发表时间: 2018
• 期刊: Theranostics
• 影响因子: 12.4
• 作者: Zhang B;Tan L;Yu Y;Wang B;Chen Z;Han J;Li M;Chen J;Xiao T;Ambati BK;Cai L;Yang Q;Nayak NR;Zhang J;Fan X
• 通讯作者: Fan X

VEGF may contribute to macrophage recruitment and M2 polarization in the decidua.

• DOI: 10.1371/journal.pone.0191040
• 发表时间: 2018
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Wheeler KC;Jena MK;Pradhan BS;Nayak N;Das S;Hsu CD;Wheeler DS;Chen K;Nayak NR
• 通讯作者: Nayak NR

Development of A 3D Tissue Slice Culture Model for the Study of Human Endometrial Repair and Regeneration.

开发用于研究人类子宫内膜修复和再生的 3D 组织切片培养模型。

• DOI: 10.3390/biom10010136
• 发表时间: 2020
• 期刊: Biomolecules
• 影响因子: 5.5
• 作者: Muruganandan,Shanmugam;Fan,Xiujun;Dhal,Sabita;Nayak,NiharR
• 通讯作者: Nayak,NiharR

Contribution of macrophages to fetomaternal immunological tolerance.

• DOI: 10.1016/j.humimm.2021.02.013
• 发表时间: 2021-05
• 期刊: Human immunology
• 影响因子: 2.7
• 作者: Parasar P;Guru N;Nayak NR
• 通讯作者: Nayak NR

Proteomic Profiling and Pathway Analysis of Acid Stress-Induced Vasorelaxation of Mesenteric Arteries In Vitro.

• DOI: 10.3390/genes13050801
• 发表时间: 2022-04-29
• 期刊: GENES
• 影响因子: 3.5
• 作者: Mohanty, Ipsita;Banerjee, Sudeshna;Mahanty, Arabinda;Mohanty, Sasmita;Nayak, Nihar Ranjan;Parija, Subas Chandra;Mohanty, Bimal Prasanna
• 通讯作者: Mohanty, Bimal Prasanna