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

基本信息

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
项目类别：
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

项目摘要

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（由应用提供）：胶质母细胞瘤多形（GBM）是成年人中最常见的原发性恶性脑肿瘤，而在最致命的癌症中，部分归因于治疗性耐药性和肿瘤复发。一个令人信服的理由治疗发展已证明挑战是GBM的异质性质。这些mAlignancys包含一个称为脑肿瘤启动的肿瘤细胞子集（BTICS），由于能够促进肿瘤血管生成并具有非肿瘤神经元细胞的某些特性，它们高度肿瘤。 BTIC具有独特的能力，可以在不同的肿瘤微环境中生存，其特征是血管或坏死/低氧壁ni。坏死/低氧壁ches含有大于生理规范的酸度水平，低细胞外pH值有助于肿瘤的生长和BTIC表型的富集。尚未阐明导致这些微环境压力的表观遗传机制。在这项研究中，将研究已被鉴定为染色质重塑剂的分子靶标，以确定其在确定血管生成中的作用。我们还将针对酸性肿瘤微环境，以确定肿瘤内pH的调节是否可以对治疗策略有好处。通过这项研究，我们希望对酸性微环境对表观遗传变化的贡献有更深入的了解，并制定一种新型的治疗策略来靶向患者疗法中的血管生成。