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Mapping the Time Course of mTORC1-Driven Tumorigenesis in the Developing Brain

绘制发育中大脑中 mTORC1 驱动的肿瘤发生的时间进程

基本信息

批准号：
10672049
负责人：
Laura Catherine Geben
金额：
$ 0.25万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-28 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10672049
关键词：
Adult Affect Benign Binding Proteins Brain Brain Neoplasms Cell Cycle Cell Differentiation process Cell Proliferation Cell Size Cell model Cells Cerebrum Characteristics Clinical Complex Custom Cytometry Cytostatics Data Development Disease Disease model Dorsal Early Diagnosis Embryo Embryonic Development Etiology Eukaryotic Initiation Factors Event FRAP1 gene Flow Cytometry Genes Genetic Transcription Glean Goals Growth Health Human Image Cytometry In Vitro Knowledge Lead Magnetic Resonance Imaging Maps Measures Mediator of activation protein Microscopy Mitotic Mitotic Activity Modeling Mus Mutate Mutation Neurodevelopmental Disorder Newborn Infant Organoids Pathway interactions Patients Pattern Pharmacology Phosphoproteins Phosphorylation Phosphotransferases Population Positioning Attribute Predisposition Prevention Process Proteins Regulation Research Research Project Grants Resected Ribosomal Protein S6 Role Signal Pathway Signal Transduction Subependymal Giant Cell Astrocytoma TSC2 gene Testing Therapeutic Intervention Time TimeLine Training Translating Tuberous Sclerosis Ventricular Wild Type Mouse Work antibody conjugate body system cell growth developmental disease human model in vivo induced pluripotent stem cell inhibitor insight loss of function loss of function mutation mTORopathies mouse model mutant nerve stem cell neurodevelopment neurogenesis novel pediatric patients perinatal development postnatal postnatal development prenatal prevent stem cell fate stem cell niche subventricular zone tumor tumor growth tumorigenesis tumorigenic

项目摘要

SUMMARY The mammalian target of rapamycin complex 1 (mTORC1) signaling pathway regulates cell size and growth and is frequently mutated in disease, including in a class of neurodevelopmental disorders known as “mTORopathies.” One such disorder, Tuberous Sclerosis Complex (TSC), affects nearly 1 in every 6,000 newborns and is characterized by the growth of benign tumors throughout the body. TSC is caused by an inactivating mutation in the genes that encode the negative regulators of mTORC1, leading to protein loss of function, hyperactivation of mTORC1, and increased cell proliferation through phosphorylation of ribosomal protein S6 (p-S6) and eukaryotic translation initiation factor 4E-binding protein 1 (p-4EBP1). Twenty percent of TSC patients develop a large tumor that preferentially presents near the ventral region of the ventricular- subventricular zone (V-SVZ), the largest neural stem cell niche in the adult brain. Recent studies of neural stem cells in the V-SVZ revealed variable transcriptional and functional capabilities corresponding to a cell’s position along the dorsoventral axis of the V-SVZ, including differential activation of mTORC1 and susceptibility to TSC tumor formation. Further, different populations of neural stem cells in the niche are mitotically active at different times throughout pre- and postnatal neural development. Postnatally, mTORC1 has been shown to be important in regulating neural stem cell quiescence, but mTORC1 signaling in the prenatal V-SVZ and its effect on quiescence in embryonic neural stem cells has not been investigated. The goal of this project is to determine the developmental stage when differential mTORC1 activity emerges along the dorsoventral axis of the V-SVZ and the extent to which dysregulated mTORC1 signaling alters cell fate. The central hypothesis of this project is that levels of mTORC1-dependent p-4EBP1, but not p-S6, determine both a prenatal neural stem cell's mitotic activity and susceptibility to TSC tumor development. To test this hypothesis, an inducible mouse model and pharmacologic agents will be used to manipulate mTORC1 signaling during embryogenesis. To map the emergence of differences in mTORC1 activity in healthy and disease states, per-cell levels of mTORC1-dependent phosphorylation events will be quantified via imaging and flow cytometry analyses of embryonic neural stem cells. To compare results across species and platforms, mTORC1-dependent signaling will be quantified in cerebral organoid models grown from induced pluripotent stem cells derived from TSC patients. Through this project, I will build upon my prior training to evaluate cell signaling and differentiation in human and mouse models of disease. Results of this work will determine the role of mTORC1 in regulating prenatal neural stem cell fate in health and disease. Clinically, this work will provide a greater understanding of the dysregulated signaling mechanisms that lead to perinatal development of tumors in the V-SVZ and identify potential suitable time points for therapeutic interventions for patients with TSC and other mTORopathies.

总结