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

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