Investigating the Effects of Stem Cell Positional Identity on Brain Tumor Development

研究干细胞位置同一性对脑肿瘤发展的影响

• 批准号: 9256911
• 负责人: Gabrielle Rushing
• 金额: $ 2.87万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-01 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9256911
• 关键词: Ablation; Acute; Adenoviruses; Adult; Affect; Alleles; Automobile Driving; Benign; Biological; Brain; Brain Neoplasms; Brain region; Cell Culture Techniques; Cell Proliferation; Cell Size; Cells; Childhood; Clinical; Collaborations; Complement; Cultured Cells; Data; Development; Disease; Dorsal; Event; FRAP1 gene; Flow Cytometry; Future; Genes; Goals; Growth; Heterogeneity; Heterotopic Transplantation; Human; Hyperactive behavior; Injectable; Injection of therapeutic agent; Left; Life; Location; Measures; Metabolic; Microscopy; Modeling; Mus; Mutation; Neonatal; Neurodevelopmental Disorder; Neuroepithelial, Perineurial, and Schwann Cell Neoplasm; Nodule; Pathway interactions; Patients; Phosphorylation; Positioning Attribute; Pre-Clinical Model; Predisposition; Property; Proteins; Protocols documentation; Reporter; Research; Research Personnel; SHH gene; Signal Transduction; Sirolimus; Stem cells; Structure; Subependymal; Subependymal Giant Cell Astrocytoma; Subgroup; TSC1 gene; TSC1/2 gene; TSC2 gene; Tamoxifen; Techniques; Testing; Tissues; Translations; Transplantation; Tuberous sclerosis protein complex; Tumor-Derived; Viral; Wild Type Mouse; Work; base; cell growth; cohort; experience; experimental study; high throughput screening; mTOR Inhibitor; mTOR Signaling Pathway; member; mouse model; mutant; nerve stem cell; new therapeutic target; novel; novel therapeutics; postnatal; progenitor; prognostic; protein expression; red fluorescent protein; relating to nervous system; response; stem; stem cell niche; stem cell population; subventricular zone; therapeutic candidate; tool; transcriptomics; tumor

PROJECT SUMMARY The broad, long-term objectives are to understand how heterogeneity within stem cell populations affects disease states and tumor development in the brain. The goal of the proposed project is to investigate how stem/progenitor cells within different regions of the brain can differentially contribute to the formation of brain tumors in Tuberous Sclerosis Complex (TSC). TSC is a disease of hyperactive mTOR pathway activity, resulting in increased cell size, survival and proliferation. TSC patients may develop either of two tumor types within the within the subventricular zone (SVZ), the largest stem cell niche in the adult and pediatric brain. They can develop small benign asymptomatic tumors, called subependymal nodules (SENS) or develop larger potentially life-threatening tumors, termed subependymal giant cell astrocytomas (SEGAs). Clinically, these tumor types are distinguished by size and location, with SEGAs being larger and restricted to the ventral SVZ. Despite clear prognostic differences, the mechanisms driving location-specific, larger tumor development are not well understood. Recent work has determined that the stem and progenitor cells within the SVZ have a positional identity- their location within the niche can predict the type of progeny they create. This property appears to be intrinsic as the cells retain their potential upon transplantation. This new information presents an intriguing possibility that SEGAS, which are thought to form from SVZ stem/progenitor cells, may reflect the properties of their location of origin. Additionally, the location of a stem/progenitor cell may determine its susceptibility to mutations in TSC1/2. The overarching hypothesis is that cell-intrinsic, region-specific differences in stem/progenitor-cell signaling promote the formation of location-specific tumors in the brain. The specific aims of this project are to (1) determine the intrinsic effects of cell location on neural tumor development in Tuberous Sclerosis Complex and (2) dissect the mTOR signaling pathway components that differ between dorsal and ventral neural stem/progenitor cells. To accomplish these aims, we will use a conditional mouse model of TSC in combination with localized Cre activity to test the combination of specific stem/progenitor cell subgroups to larger tumor formation. In tandem with this model, we will use primary stem cell cultures to examine mTOR signaling in wild type and mutant cells using both microscopy and a novel flow- cytometry based approach. To achieve the proposed work, we are incorporating a clinical experience with our collaborator Dr. Kevin Ess, collaboration with a world expert in phospho-specific flow cytometry (Dr. Jonathan Irish) and utilizing our lab’s unique technique of targeting subpopulations within the stem cell niche. The proposed research is highly relevant as it will reveal novel information regarding the origin of TSC brain tumors. Additionally, this work is broadly applicable to many fields as it investigates how stem cells can possess differential basal metabolic programming and potential to signal through growth pathways depending on their location within a stem cell niche.

项目总结