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Regulation of Angpt1 and DIPG blood-brain barrier integrity by H3K27M mutations

H3K27M 突变对 Angpt1 和 DIPG 血脑屏障完整性的调节

基本信息

批准号：
10538616
负责人：
Timothy N Phoenix
金额：
$ 40.81万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-15 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10538616
关键词：
Adult Affinity Agonist Angiopoietins Astrocytes Blood Blood - brain barrier anatomy Blood Vessels Blood brain barrier dysfunction Brain Brain Neoplasms CRISPR/Cas technology Cell Lineage Cells Childhood Childhood Brain Neoplasm Clinical Trials Data Development Diffuse intrinsic pontine glioma Disease Electroporation Endothelium Future Gene Expression Profile Genetic Transcription Genome Genomics Glioma H3 K27M mutation Histologic Human Knock-out Link Location Maintenance Malignant Glioma Malignant neoplasm of brain Methods Modeling Molecular Mus Mutation Oligodendroglia Pathogenesis Pathway interactions Patient-Focused Outcomes Patients Pattern Pharmaceutical Preparations Phenotype Play Recurrence Regulation Reporter Role Signal Pathway Signal Transduction Specific qualifier value TIE-2 Receptor Techniques Testing Therapeutic Treatment outcome Tumor Subtype Work angiogenesis antagonist blood-brain barrier function blood-brain barrier penetration cell type differential expression efficacious treatment experimental study gain of function glioma cell line high throughput screening improved in utero in vivo inhibitor insight loss of function molecular subtypes mouse model neoplastic cell nervous system disorder oligodendrocyte progenitor overexpression patient stratification preclinical trial predicting response progenitor programs response to injury small molecule stem cells therapy resistant tool transgene expression treatment and outcome treatment strategy tumor whole genome

项目摘要

Malignant gliomas encompass a diverse set of diseases, including pediatric and adult high-grade gliomas. Recent genomic profiling techniques have advanced our understanding of these tumors by identifying molecular subtypes and recurrent mutations, yet treatment options remain limited. The blood-brain barrier (BBB) is commonly cited as a major factor in treatment resistance since the majority of drugs and small molecules display limited BBB penetration. Advancing our understanding of the cellular and molecular mechanisms that regulate brain tumor BBB function will be crucial to improve treatment strategies and outcomes for patients. Our recent work demonstrated that BBB integrity can be dictated by brain tumor subtype specific mutations. In preliminary studies using diffuse intrinsic pontine glioma (DIPG) and cortical high-grade glioma (HGG) mouse models we have created by in utero electroporation (IUE), we identified differences in Angiopoietin1 (Angpt1) expression, a high affinity agonist of the endothelial Tie2 receptor. The Angpt1-Tie2 signaling axis plays a key role in vascular response to injury, but its endogenous expression and function in brain tumors not been thoroughly evaluated. Preliminary data in human tumors and mouse models reveal Angpt1 expression is elevated in glial brain tumors, and displays differences within glioma subtypes. These differences mirror Angpt1 expression patterns we have found in normal brain development, suggesting expression in gliomas may be linked in part to cell state programs or upstream signaling pathways that promote particular cell states. Initial experiments in IUE DIPG mouse models have shown that overexpression of the Tie2 antagonist Angpt2, or knockout of Angpt1, result in vascular alterations. These findings form the basis of our hypothesis that Angpt1 is differentially expressed in gliomas, and that its endogenous expression participates in regulating high-grade glioma blood-brain barrier integrity. To test our hypothesis, we propose the following aims: (1) Define the expression and function of Angpt1 in high- grade glioma blood-brain barrier integrity. In this aim we will (1A) determine the cellular expression pattern of Angpt1 within gliomas, (1B,C) perform a detailed analysis of BBB, vascular phenotype and transcriptional signatures to determine the role of endogenous Angpt1 in glioma BBB integrity, and (1D) assess how differences in endogenous Angpt1 expression between glioma subtypes impacts current therapeutic strategies that target this signaling axis. Aim 2 will determine the mechanisms that regulate Angpt1 expression. We will examine the influence of cell lineage states and upstream signaling determinants, along with applying unbiased genome level screens to define regulators of Angpt1. The proposed set of experiments will significantly improve our understanding of how brain tumors regulate BBB integrity, and the dynamic interactions that occur between brain tumor cells and their microenvironment. Taken together, the results and tools generated will yield new insights into the expression and function of Angpt1, with broader implications relevant to other brain cancers and neurological disorders that involve vascular alterations and BBB dysfunction.

恶性神经胶质瘤包括多种疾病，包括小儿和成人高级别神经胶质瘤。最近的基因组分析技术通过鉴定分子水平，亚型和复发突变，但治疗选择仍然有限。血脑屏障（BBB）通常被认为是治疗耐药性的主要因素，因为大多数药物和小分子表现出有限的BBB渗透。推进我们对调节细胞和分子机制的理解，脑肿瘤血脑屏障功能将是至关重要的，以改善治疗策略和患者的结果。我们最近研究表明，BBB完整性可由脑肿瘤亚型特异性突变决定。初步使用弥漫性内在脑桥胶质瘤（DIPG）和皮质高级别胶质瘤（HGG）小鼠模型的研究，通过子宫内电穿孔（IUE），我们确定了血管生成素1（Angpt 1）表达的差异，内皮Tie 2受体的高亲和力激动剂。Angpt 1-Tie 2信号轴在血管生成中起着关键作用。对损伤的反应，但其在脑肿瘤中的内源性表达和功能尚未得到彻底评估。人类肿瘤和小鼠模型的初步数据显示，Angpt 1表达在神经胶质脑肿瘤中升高，并显示胶质瘤亚型之间的差异。这些差异反映了Angpt 1的表达模式，在正常的大脑发育中发现，这表明在胶质瘤中的表达可能部分与细胞状态程序有关或上游信号通路来促进特定的细胞状态。IUE DIPG小鼠中的初始实验模型显示，Tie 2拮抗剂Angpt 2的过表达或Angpt 1的敲除导致血管内皮细胞的凋亡，改变。这些发现构成了我们假设Angpt 1在胶质瘤中差异表达的基础，并且其内源性表达参与调节高级别胶质瘤血脑屏障的完整性。到为了验证我们的假设，我们提出以下目标：（1）明确Angpt 1在高血压大鼠中的表达和功能，级别胶质瘤血脑屏障完整性。在这个目标中，我们将（1A）确定以下的细胞表达模式： Angpt 1在神经胶质瘤中的表达，（1B，C）对血脑屏障、血管表型和转录水平进行了详细的分析。特征，以确定内源性Angpt 1在神经胶质瘤BBB完整性中的作用，以及（1D）评估差异如何神经胶质瘤亚型之间内源性Angpt 1表达影响目前的治疗策略，这个信号轴目的2将确定调节Angpt 1表达的机制。我们会研究细胞谱系状态和上游信号决定簇的影响，沿着应用无偏基因组水平筛选以定义Angpt 1的调节因子。拟议的一系列实验将大大改善我们的了解脑肿瘤如何调节血脑屏障的完整性，以及脑肿瘤之间发生的动态相互作用。肿瘤细胞及其微环境综合考虑，所产生的结果和工具将产生新的见解 Angpt 1的表达和功能，与其他脑癌相关的更广泛的影响，涉及血管改变和BBB功能障碍的神经系统疾病。