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

摘要法 某些侵袭性相关的母胎疾病（IMFD）的发生是由于缺乏或过度 胎盘侵入子宫内膜。这些都是严重的情况，有时需要手术 干预措施，包括子宫切除术，并导致症状，包括胎儿生长受限， 先兆子痫导师（Kshitiz，UConn Health）和合作者（Profs.列夫琴科 和Gunter，Yale）研究不同胎盘表型的进化历史， 子宫内膜间质成纤维细胞（ESFs）在控制浸润程度中的核心作用。的 我提出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-滋养层信号传导对这种调节的影响，随着I的增加， 开始我的独立研究生涯所需的培训和经验。在K99阶段， 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加强， 从我的导师在系统生物学方法的培训，构成了一个闭环方法 结合表型分析、理论建模、实验验证、假设细化 反馈到实验研究中探索适合胎盘生长调节的模型 入侵真兽目哺乳动物了解IMFD，我已经从数学映射， 实验验证了胎盘侵入深度变化的基因组基础， 调节分子如GATA 2和TFDP 1。此外，我发现了基质侵袭性基因 可以在不同组织类型中保留，ESF中胎盘侵袭与ESF中胎盘侵袭之间的影响一致 黑色素瘤侵入皮肤成纤维细胞。这为阐明细胞凋亡的分子机制开辟了途径。 ESF-滋养层信号对间质侵袭调节的影响，可能具有平行机制 IMFD中潜在的失调侵袭。利用生物信息学，生物工程分析，数学 我发现并验证了绒毛外滋养层细胞（EVT）分泌的IL 11对 通过SOCS 3的蜕膜ESF侵袭性和MMP 1产生。我也会探索 人子宫内膜内的亚群与侵入的EVT相互作用，下游的细胞亚群与侵入的EVT相互作用。 这种相互作用的信号效应。将对通过这些方法鉴定的所有分子组分进行验证 在一个生物工程的体外基质侵袭试验中，我在功能上进行了改进， 基因型与特定侵袭相关的亚特征。另一个微加工技术平台， 我与导师共同开发的将增强推断EVT-ESF旁分泌串扰的序列。 在我的R 00阶段，我将通过以下方式建立信息学数学模型来预测IMFD结果： 将来自我的两个K99 aim的模型与患者样本ESF测序数据的深入分析相结合