Mapping inter-cellular trophoblast-decidual signaling to its effects on invasion related maternal-fetal diseases

绘制细胞间滋养层-蜕膜信号传导及其对侵袭相关母胎疾病的影响

• 批准号: 10523623
• 负责人: Yasir Suhail
• 金额: $ 11.77万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10523623
• 关键词: Achievement; Affect; Automobile Driving; Back; Behavior; Bioinformatics; Biological Assay; Biomedical Engineering; Cells; Cesarean section; Characteristics; Computational Biology; Computer Models; Cyclic AMP-Dependent Protein Kinases; Data; Decidua; Decidual Cell Reactions; Disease Outcome; Endometrial; Endometrium; Equilibrium; Etiology; Fetal Diseases; Fetal Growth Retardation; Fibroblasts; Foundations; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Screening; Genetic Transcription; Genomics; Genotype; Health; Homeostasis; Human; Hysterectomy; IGFBP4 gene; In Vitro; Informatics; Interstitial Collagenase; Invaded; Investigation; Life; Mammals; Maps; Maternal-Fetal Exchange; Mathematics; Mentors; Methodology; Methods; Modeling; Molecular; Mothers; Operative Surgical Procedures; Outcome; Paracrine Communication; Pathologic; Pathway interactions; Patients; Phase; Phenotype; Physiological; Physiology; Placenta; Placenta Accreta; Placental Insufficiency; Placentation; Play; Population; Pre-Eclampsia; Pregnancy; Production; Recording of previous events; Regulation; Regulatory Element; Research; Resistance; Risk; Role; Sampling; Side; Signal Transduction; Skin; Statistical Models; Stromal Invasion; Symptoms; System; Systems Biology; Technology; Testing; Theoretical model; Tissues; Training; Transcriptional Regulation; Uterus; Validation; Variant; Work; base; career; comparative; early onset; endometrial stroma; experience; experimental study; feeding; fetus cell; inhibitor; mathematical model; melanoma; network models; paracrine; precision medicine; programs; single cell analysis; single-cell RNA sequencing; transcriptome sequencing; transcriptomics; trophoblast

Abstr act Certain invasion-related maternal-fetal diseases (IMFDs) occur due to either insufficient or excessive placental invasion into the endometrium. These are serious conditions, sometimes requiring surgical interventions including hysterectomies, and leading to symptoms including fetal growth restriction and preeclampsia. Previous work from the mentor (Kshitiz, UConn Health) and collaborators (Profs. Levchenko and Gunter, Yale) studying the evolutionary history of diverse placental phenotypes has established the central role of the endometrial stromal fibroblasts (ESFs) in controlling the extent of the invasion. The proposed training and research plan will allow me to study the molecular basis of the endometrial stromal control of placental invasion, including the effect of ESF-trophoblast signaling on this regulation, as I gain the training and experience needed to launch my independent research career. During the K99 phase, my previous training and experience in bioinformatics and computational biology will be augmented by training from my mentor in the systems biology approach, constituting a closed loop methodology combining phenotypic assays, theoretical modeling, experimental validation, hypothesis refinement feeding back into experimental investigations. Exploiting the apposite model of the regulation of placental invasion in eutherian mammals to understand IMFDs, I have since mathematically mapped and experimentally validated the genomic basis of this variation in depth of placental invasion through specific regulatory molecules such as GATA2 and TFDP1. Further, I found evidence that stromal invasability genes could be conserved across tissue types, with congruent effects between placental invasion in ESFs and melanoma invasion into skin fibroblasts. This opens avenues for delineating the molecular mechanisms of ESF-trophoblast signaling effects on the stromal regulation of invasion, with likely parallel mechanisms underlying dysregulated invasion in IMFDs. Using bioinformatics, bioengineered assays, mathematical modeling I found and validated the effect of IL11s secreted by extravillous trophoblasts (EVTs) on the decidual ESF invasability and MMP1 production through SOCS3. I will also explore how different subpopulations within the human endometrium interact with the invading EVTs, and the downstream signaling effect of this interaction. All molecular components identified by these methods will be validated on a bioengineered in-vitro stromal invasion assay, functionally advanced by me, to map the stromal genotype to specific invasion related sub-characteristics. Another microfabricated technology platform, that I co-developed with the mentor will be augmented to infer the sequential EVT-ESF paracrine cross-talk . During my R00 phase I will build informatics-mathematical models to predict IMFD outcomes by integrating models from my two K99 aims with deep analysis of patient sample ESF sequencing data

节制行为 某些侵袭性母婴疾病(IMFD)的发生是由于不足或过多。 胎盘侵入子宫内膜。这些情况都很严重，有时需要动手术。 包括子宫切除术在内的干预措施，并导致胎儿生长受限和 先兆子痫。导师(Kshitiz，UConn Health)和合作者(教授)之前的工作。列夫琴科 和耶鲁大学冈特)研究不同胎盘表型的进化史，建立了 子宫内膜间质成纤维细胞(ESF)在控制侵袭程度中的中心作用。这个 拟议的培训和研究计划将使我能够研究子宫内膜间质的分子基础 胎盘侵袭的控制，包括ESF-滋养层细胞信号对这种调节的影响，随着I的增加 开始我的独立研究事业所需的培训和经验。在K99阶段，我的 以前在生物信息学和计算生物学方面的培训和经验将通过 从我的导师那里接受了系统生物学方法的培训，构成了一种闭环方法 结合表型分析、理论建模、实验验证、假设改进 反馈到实验研究中。探索胎盘调节的合适模型 为了了解真兽类的入侵，我后来绘制了数学图谱，并 通过实验验证了这种胎盘侵袭深度变异的基因组基础 调节分子如GATA2和TFDP1。此外，我发现有证据表明间质侵袭性基因 可以在不同的组织类型中保守，在ESFS的胎盘侵袭和 黑色素瘤侵袭皮肤成纤维细胞。这就为描述分子机制开辟了新的途径 ESF-滋养层细胞信号在基质侵袭调控中的作用，可能存在平行机制 IMFDs潜在的不受调控的侵袭。使用生物信息学、生物工程分析、数学 模型发现并验证了绒毛外滋养层细胞分泌的IL-11对人脐静脉内皮细胞的影响。 通过SOCS3确定ESF的抗侵性和MMP1的产量。我还将探索如何不同于 人类子宫内膜内的亚群与侵袭性动静脉管相互作用，并且下游 这种相互作用的信号传递效应。通过这些方法鉴定的所有分子成分都将得到验证 关于一种生物工程的体外基质侵袭试验，由我在功能上提出，以定位基质 基因分型到特定侵袭相关亚型特征。另一个微细加工技术平台， 我与导师共同开发的将被放大，以推断EVT-ESF串扰的顺序。 在我的R00阶段，我将建立信息学-数学模型，通过以下方式预测IMFD结果 将我的两个K99目标的模型与患者样本ESF测序数据的深入分析集成在一起