Microenvironmental Regulation of Glioblastoma Angiogenesis via CHD7

CHD7 对胶质母细胞瘤血管生成的微环境调节

• 批准号: 9274829
• 负责人: Nathaniel Boyd
• 金额: $ 1.93万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2017-12-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9274829
• 关键词: Acidity; Adult; Affect; Angiogenic Factor; BAY 54-9085; Bicarbonates; Binding; Biology; Blood Vessels; Brain; Brain Neoplasms; Buffers; CHD7 gene; Cells; Chromatin; Computer Simulation; Data; Endothelial Cells; Enhancers; Epigenetic Process; FDA approved; Future; Glioblastoma; Glucose; Growth; Hypoxia; Immunohistochemistry; In Vitro; KDR gene; Knowledge; Laboratories; Lead; Link; Malignant Neoplasms; Malignant neoplasm of brain; Mediating; Messenger RNA; Modeling; Molecular Target; Monoclonal Antibodies; Mus; Nature; Necrosis; Nutrient; Oxygen; PECAM1 gene; Pathologic; Patients; Pharmacotherapy; Phenotype; Physiological; Property; Recombinant Antibody; Recurrence; Regulation; Repression; Role; Sodium-Hydrogen Antiporter; Specimen; Staining method; Stains; Stress; Testing; Therapeutic; Tissue Sample; Treatment Protocols; Tube; Tumor Angiogenesis; Tumor Initiators; Tumor-Associated Vasculature; Tumorigenicity; Vascular Endothelial Growth Factors; Vascular Proliferation; Xenograft procedure; angiogenesis; bevacizumab; cariporide; cell motility; density; epigenetic regulation; extracellular; improved; in vivo; inhibitor/antagonist; kinase inhibitor; neoplastic cell; nerve stem cell; novel; novel strategies; outcome forecast; overexpression; pH gradient; pressure; promoter; public health relevance; response; small hairpin RNA; therapeutic target; therapy development; therapy resistant; treatment response; treatment strategy; tumor; tumor growth; tumor microenvironment; tumorigenic

 DESCRIPTION (provided by applicant): Glioblastoma multiform (GBM) is the most common primary malignant brain tumor in adults and among the deadliest cancers due, in part, to therapeutic resistance and tumor recurrence. One compelling reason therapy development has proven challenging is the heterogeneous nature of GBMs. These malignancies contain a subset of tumor cells known as brain tumor initiating cells (BTICs) that are highly tumorigenic due to an ability to promote tumor angiogenesis and have some properties of non-neoplastic neural stem cells. BTICs have a unique ability to survive in a distinct tumor microenvironments characterized as either vascular or necrotic/hypoxic niches. The necrotic/hypoxic niches contain levels of acidity greater than physiologic norms, and low extracellular pH contributes to tumor growth and enriches for BTIC phenotypes. Epigenetic mechanisms contributing to these microenvironmental pressures have not been elucidated. In this study, a molecular target that has been identified as a chromatin remodeler will be investigated to determine its role in regulating angiogenesis. We will also target the acidic tumor microenvironment to determine if the modulation of intratumoral pH can be a benefit to therapeutic strategies. Through this study we hope to achieve a greater understanding of the contribution of acidic microenvironments to epigenetic changes and develop a novel treatment strategy to target angiogenesis in patient therapies.

 描述(申请人提供)：多形性胶质母细胞瘤(GBM)是成人最常见的原发恶性脑瘤，也是最致命的癌症之一，部分原因是治疗耐药和肿瘤复发。事实证明，治疗开发具有挑战性的一个令人信服的原因是基底膜的异质性。这些恶性肿瘤包含一种称为脑肿瘤启动细胞(BTIC)的肿瘤细胞亚群，由于具有促进肿瘤血管生成的能力，因此具有高度致瘤性，并具有非肿瘤性神经干细胞的一些特性。BTIC在不同的肿瘤微环境中具有独特的生存能力，其特征是血管或坏死/缺氧的利基环境。坏死/缺氧的壁龛含有高于生理正常水平的酸度，低细胞外pH有助于肿瘤生长并丰富BTIC表型。造成这些微环境压力的表观遗传机制尚未阐明。在这项研究中，一个被确认为染色质重构体的分子靶点将被研究，以确定其在调节血管生成中的作用。我们还将针对酸性肿瘤微环境来确定肿瘤内pH的调节是否有助于治疗策略。通过这项研究，我们希望更好地了解酸性微环境对表观遗传学变化的贡献，并开发一种新的治疗策略，在患者治疗中针对血管生成。