PERICYTES IN ANGIOGENESIS IN NEUROFIBROMATOSIS TYPE 1

1 型神经纤维瘤病血管生成中的周细胞

• 批准号: 6797630
• 负责人: UGUR OZERDEM
• 金额: $ 9.78万
• 依托单位: LA JOLLA INST FOR MOLECULAR MEDICINE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-03 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6797630
• 关键词: angiogenesis; angiogenesis inhibitors; animal breeding; blocking antibody; cell growth regulation; cell proliferation; embryo /fetus; genetically modified animals; histology; immunocytochemistry; laboratory mouse; longitudinal animal study; macrophage; mammalian embryology; neoplasm /cancer blood supply; neoplastic process; neurofibromatosis; neurofibromatosis type 1 protein /gene; neutralizing antibody; pharmacology; proteoglycan; vascular endothelium; xenotransplantation

DESCRIPTION (provided by applicant): Neurofibromatosis type 1 (NF1) is one of the most common inherited disorders in children. The most common and serious consequence of NF1 is the reduction of life expectancy by neoplasms. The underlying hypothesis for this proposal is that, in addition to angiogenesis mediated by tumor-derived factors, the molecular defect associated with neurofibromatosis type 1 may also promote tumor neovascularization by directly activating the proliferation of vascular pericytes. This proposal will establish pericytes and NG2 proteoglycan, which has a functional role in angiogenesis, as novel cellular and molecular targets for the anti-angiogenic treatment of NF1-associated tumors. Specific Aims: 1) To use pericyte-specific markers to delineate in detail the temporal and spatial relationship between pericytes and endothelial cells in the neovasculature of NF1-derived tumors. 2) To determine whether interference with the function of a key pericyte component, the NG2 proteoglycan, inhibits NF1 tumor vascularization and progression. This will be done through both genetic (i.e. the NG2 null mouse) and immunochemical (i.e. NG2 blocking antibody) approaches. 3) To demonstrate increased proliferation of mural cells in the micro and macrovasculature of embryonic NF1-/- mice, to document the developmental consequences of this phenomenon, and to demonstrate the possibility of rescuing these NF1-associated defects via ablation of NG2. Research Design: 1) de novo and orthotopic xenograft NF1 tumor models will be used to study the details of the vascular pericyte/endothelial cell relationship. 2) The anti-angiogenic efficacy of NG2 neutralizing antibody will be evaluated in a mouse corneal model of NF1 tumor neovascularization. In addition, a breeding strategy will be developed with NF1+/- mice and NG2 knockout mice to yield NF1+/-NG2+/+ and NF1+/- NG2-1- mice. Vascularization of orthotopic NF1-derived glioma xenografts will be compared in these two genotypes. In the absence of xenografts, the investigators will also follow these 2 groups of mice for 2 years in order to compare de novo tumor onset and progression. 3) The investigators will examine the effect of the NF1-/- and NF1-/+ genotypes on microvascularization in embryonic development. The ability of NG2 ablation to rescue micro and macrovascular defects will be determined.

描述（由申请人提供）：1型神经纤维瘤病（NF1）是儿童最常见的遗传性疾病之一。NF1最常见和最严重的后果是肿瘤导致预期寿命缩短。该建议的基本假设是，除了肿瘤衍生因子介导的血管生成外，与1型神经纤维瘤病相关的分子缺陷也可能通过直接激活血管周细胞的增殖来促进肿瘤新生血管的形成。这一提议将确立周细胞和NG2蛋白多糖作为抗血管生成治疗nf1相关肿瘤的新细胞和分子靶点。NG2蛋白多糖在血管生成中具有功能作用。具体目的：1)利用周细胞特异性标志物详细描述nf1源性肿瘤新生血管中周细胞与内皮细胞的时空关系。2)确定干扰关键周细胞成分NG2蛋白聚糖的功能是否抑制NF1肿瘤血管化和进展。这将通过遗传（即NG2无效小鼠）和免疫化学（即NG2阻断抗体）方法来完成。3)证明胚胎NF1-/-小鼠微血管和大血管壁细胞增殖增加，记录这一现象的发育后果，并证明通过消融NG2来挽救这些NF1相关缺陷的可能性。研究设计：1)采用新生和原位异种移植NF1肿瘤模型，研究血管周细胞/内皮细胞关系的细节。2)在小鼠角膜NF1肿瘤新生血管模型中评价NG2中和抗体的抗血管生成效果。此外，还将研究NF1+/-小鼠和NG2敲除小鼠的繁殖策略，以产生NF1+/-NG2+/+和NF1+/-NG2 -1-小鼠。将比较这两种基因型原位nf1衍生胶质瘤异种移植物的血管化情况。在没有异种移植物的情况下，研究人员还将对这两组小鼠进行为期2年的随访，以比较新发肿瘤的发生和进展。3)研究人员将研究NF1-/-和NF1-/+基因型对胚胎发育中微血管形成的影响。NG2消融修复微血管和大血管缺损的能力将被确定。