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

抽象的 某些与入侵相关的母胎疾病（IMFD）是由于缺乏或过度的 胎盘侵入子宫内膜。这些都是严重的情况，有时需要手术 包括子宫切除术在内的干预措施，并导致胎儿生长受限等症状 先兆子痫。导师（Kshitiz，康涅狄格大学健康学院）和合作者（Levchenko 教授）之前的工作 和耶鲁大学的冈特）研究不同胎盘表型的进化史已经建立了 子宫内膜基质成纤维细胞（ESF）在控制侵袭程度方面发挥着核心作用。这 拟议的培训和研究计划将使我能够研究子宫内膜基质的分子基础 控制胎盘侵袭，包括 ESF-滋养层信号传导对此调节的影响，正如我所获得的 开展我的独立研究生涯所需的培训和经验。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得到增强 我的导师对系统生物学方法进行了培训，构成了闭环方法 结合表型测定、理论建模、实验验证、假设完善 反馈到实验研究中。开发胎盘调节的适当模型 为了理解IMFD，我从数学上绘制了真兽类哺乳动物的入侵并 通过特定的实验验证了胎盘侵袭深度变化的基因组基础 调节分子，例如 GATA2 和 TFDP1。此外，我发现了基质侵袭性基因的证据 可以在不同组织类型中保守，ESF 中的胎盘侵袭和 黑色素瘤侵入皮肤成纤维细胞。这为描述分子机制开辟了途径 ESF-滋养层信号传导对侵袭基质调节的影响，可能具有平行机制 IMFD 中潜在的失调入侵。利用生物信息学、生物工程分析、数学 通过建模，我发现并验证了绒毛外滋养细胞 (EVT) 分泌的 IL11 对 通过 SOCS3 观察蜕膜 ESF 的侵袭性和 MMP1 的产生。我还将探讨如何不同 人类子宫内膜内的亚群与入侵的 EVT 相互作用，下游 这种相互作用的信号效应。通过这些方法鉴定的所有分子成分都将得到验证 由我在功能上先进的生物工程体外基质侵袭测定，以绘制基质 基因型与特定入侵相关的子特征。另一个微加工技术平台 我与导师共同开发将增强推断顺序EVT-ESF旁分泌串扰。 在 R00 阶段，我将建立信息学数学模型来预测 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相结合