Bone marrow derived neural stem cell therapy for glioma

骨髓源性神经干细胞治疗神经胶质瘤

基本信息

批准号：
8184969
负责人：
John S Yu
金额：
$ 36.53万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8184969
关键词：
AMD3100 Adhesions Adult Antibodies Apoptosis Area Autologous Beryllium Binding Biological Biological Assay Blood Vessels Bone Marrow Bone Marrow Cells Brain Brain Neoplasms CXCL12 gene CXCR4 Receptors CXCR4 gene Capillary Endothelial Cell Cells Conditioned Culture Media Cytolysis Cytotoxic T-Lymphocytes Cytotoxic agent Endothelial Cells Endothelium Engraftment Epidermal Growth Factor Epidermal Growth Factor Receptor Genes Glioblastoma Glioma Grant Harvest Hippocampus (Brain)Home environment Homing Human Immunologics Implant In Vitro Individual Inflammatory Injury Integrins Mediating Microsatellite Repeats Modeling Mus Neoplasms Nervous system structure Neurodegenerative Disorders Pathologic Pathway interactions Property Receptor Signaling Rodent Role Signal Transduction Source Stem cell transplant Stem cells Stream Stromal Cell-Derived Factor 1 Structure Surface T cell response Testing Therapeutic Agents Tissues Transgenic Organisms Translating Tropism Tumor Burden Ursidae Family cancer stem cell cell motility cellular engineering effective therapy in vivo inhibitor/antagonist migration neoplastic cell nerve stem cell receptor relating to nervous system self-renewal stem stem cell biology stem cell therapy subventricular zone trafficking tumor

项目摘要

DESCRIPTION (provided by applicant): Current therapies for glioblastoma are unable reach tumor cells that insinuate themselves within neural structures. However, the obstacles to effective therapy match the known biological properties of the abundant and autologous source of bone marrow derived neural stem cells (BM-NSCs). Understanding the mechanisms by which stem cells home to tumor cells and other areas of injury is important not only to understand basic stem cell biology but also to translate stem cell therapies for brain tumors and neurodegenerative disorders. Our central hypothesis is that the mechanisms that govern bone marrow derived neural stem cell (BM-NSC) tropism toward the glioma vascular niche are identical to those that mediate NSC migration to and from the homeostatic vascular niche. We will test the hypothesis that SDF-1 mediates the migration of BM-NSCs toward the pathological vascular niche of gliomas and that cancer stem cell migration is SDF-1 dependent, rendering these cells "co-travelers" in the brain. We propose to: AIM 1: Test the hypothesis that BM-NSC migration to the tumor vascular niche is dependent on CXCR4 expression, CXCR4 interaction with SDF-1, CXCR4 receptor signaling, and downstream induction of the PI3K/Akt pathway in a transgenic spontaneous glioma model. AIM 2: Test the hypothesis that SDF1 will increase a6 integrin expression and EGFR expression on BM-NSCs and that this effect will increase the adhesion of BM-NSCs to the surface of tumor endothelium and increase tropism toward tumor conditioned media, respectively in vitro. In a spontaneous glioma model, we will test the hypothesis that blocking a6 integrin will separate the cells from their tumor vascular niche. We will also test the hypothesis that blocking EGFR will limit the migratory potential of BM-NSCs. AIM 3: Test the hypothesis that CSC invasion to the tumor vascular niche is CXCR4 dependent. Test the hypothesis that BM-NSCs and CSCs co-localize within the glioma vascular niche in a spontaneous transgenic murine model of glioma. PUBLIC HEALTH RELEVANCE: This grant proposes to study bone marrow derived neural stem cell (BM-NSC) migration to the tumor vascular niche by studying mechanisms mediated by the SDF-1 signal from the tumor vascular niche as it binds its receptor CXCR4 on BM-NSCs. We will investigate those mechanisms that mediate neural stem cell migration in the vascular niche which we hypothesize will parallel those that draw BM-NSCs to the pathologic tumor vascular niche. By studying the role of each of these mechanisms in BM-NSC migration to the tumor vascular niche, we may better be able to utilize these cells to deliver cytotoxic agents to glial tumor cells.

描述（由申请人提供）：目前的胶质母细胞瘤疗法无法到达潜入神经结构内的肿瘤细胞。然而，有效治疗的障碍与丰富的自体骨髓源性神经干细胞 (BM-NSC) 的已知生物学特性相匹配。了解干细胞归巢到肿瘤细胞和其他损伤区域的机制不仅对于了解基本干细胞生物学很重要，而且对于转化脑肿瘤和神经退行性疾病的干细胞疗法也很重要。我们的中心假设是，控制骨髓源性神经干细胞（BM-NSC）向神经胶质瘤血管生态位的趋向性的机制与介导 NSC 迁移至稳态血管生态位和从稳态血管生态位迁移的机制相同。我们将检验以下假设：SDF-1 介导 BM-NSC 向神经胶质瘤的病理性血管生态位迁移，并且癌症干细胞迁移是 SDF-1 依赖性的，使这些细胞成为大脑中的“同路人”。我们建议：目标 1：测试以下假设：BM-NSC 向肿瘤血管微生境的迁移依赖于 CXCR4 表达、CXCR4 与 SDF-1 的相互作用、CXCR4 受体信号传导以及转基因自发组织中 PI3K/Akt 通路的下游诱导。神经胶质瘤模型。目标 2：测试以下假设：SDF1 将增加 BM-NSC 上的 a6 整合素表达和 EGFR 表达，并且这种作用将分别在体外增加 BM-NSC 与肿瘤内皮表面的粘附并增加对肿瘤条件培养基的向性。在自发性神经胶质瘤模型中，我们将测试阻断 a6 整合素将使细胞与其肿瘤血管生态位分离的假设。我们还将测试阻断 EGFR 将限制 BM-NSC 迁移潜力的假设。目标 3：检验 CSC 侵入肿瘤血管微环境依赖 CXCR4 的假设。在自发转基因小鼠神经胶质瘤模型中检验 BM-NSC 和 CSC 在神经胶质瘤血管生态位内共定位的假设。公共健康相关性：这项拨款提议通过研究来自肿瘤血管生态位的 SDF-1 信号介导的机制来研究骨髓源性神经干细胞 (BM-NSC) 向肿瘤血管生态位的迁移，因为 SDF-1 信号与 BM-NSC 上的受体 CXCR4 结合。国家干细胞。我们将研究介导神经干细胞在血管生态位中迁移的机制，我们假设这些机制与将 BM-NSC 吸引到病理性肿瘤血管生态位的机制类似。通过研究这些机制在 BM-NSC 迁移到肿瘤血管生态位中的作用，我们可能能够更好地利用这些细胞向神经胶质瘤细胞递送细胞毒性药物。