Role of Neurotrophin Receptors in Neuroblastoma
神经营养蛋白受体在神经母细胞瘤中的作用
基本信息
- 批准号:6654414
- 负责人:
- 金额:$ 25.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2001
- 资助国家:美国
- 起止时间:2001-07-01 至 2006-06-30
- 项目状态:已结题
- 来源:
- 关键词:Adenoviridae angiogenesis athymic mouse autocrine cell differentiation fibroblasts growth factor receptors hypoxia immunocytochemistry metastasis mitogen activated protein kinase neoplastic growth neuroblastoma neurotrophic factors oncoproteins paracrine transfection /expression vector vascular endothelial growth factors
项目摘要
DESCRIPTION: (Adapted from the investigator's abstract) Neuroblastoma has a
wide spectrum of clinical behavior, with tumors regressing spontaneously in
infants, to widely metastatic disease and poor outcome despite intensive
chemotherapy and bone marrow transplantation. The biological mechanism for
these disparate clinical behaviors is likely to involve the neurotrophin
receptors TrkA, TrkB, and TrkC, and their respective ligands, NGF, BDNF, and
NT3. Favorable neuroblastomas express TrkA and TrkC, but not NGF or NT3. In
contrast, unfavorable, metastatic neuroblastomas express TrkB and BDNF. Based
on these observations we have proposed a model in which TrkA and TrkC promote
favorable neuroblastoma by inducing neuronal d~(ferentiation, while an
autocrine loop of TrkB and BDNF promotes unfavorable neuroblastoma by enhancing
tumor growth, cell survival, and metastasis. In support of this model, studies
have shown that TrkA and TrkC can induce neuronal differentiation, that TrkB
can increase cell survival, stimulate cell invasiveness, and is
chemoprotective. TrkB can also increase the expression of vascular endothelial
growth factor (VEGF), suggesting that TrkB can induce angiogenesis, a critical
step in tumor proliferation and metastases. The overall goal of this grant to
obtain in vivo evidence for the Trk-NBL model. Our experiments will focus on
TrkB and the autocrine/paracrine loop formed with BDNF, with the results
compared with TrkC and NT3. For the in vivo studies we will use a xenograft
model in the nude mouse that we have developed in our laboratory that produces
large primary tumors and metastases to lung, liver, or bone marrow. Aim 1. We
hypothesize that in vivo, TrkB promotes cell survival, proliferation, and
metastases, while TrkC promotes differentiation. We will compare the ability of
TrkB and TrkC to promote cell survival, tumor growth, metastases,
differentiation, and protect against chemotherapy in vivo. Aim 2. We
hypothesize that an autocrine or paracrine loop of BDNF/TrkB or NT3/TrkC
promotes cell survival and differentiation. We will determine if autocrine
expression of BDNF or NT3 in neuroblastoma cell lines or fibroblasts promotes
differentiation or survival. Aim 3. We hypothesize that Trk receptors regulate
angiogenesis in neuroblastoma. We will determine if TrkB and TrkC regulate the
expression of VEGF and determine the signal pathways involved. We will
determine if TrkB and TrkC protect neuroblastoma against hypoxia induced by
anti-VEGF agents. By systematically comparing TrkB with TrkC in vivo, these
studies will allow us to determine the validity of the Trk-NBL model.
描述:(改编自研究者的摘要)神经母细胞瘤有一个
临床表现广泛,肿瘤自发退行性变
婴儿,转移性疾病广泛,尽管病情严重,但结局不佳
化疗和骨髓移植。致病的生物学机制
这些不同的临床行为可能涉及神经营养因子
受体TrkA、TrkB和TrkC及其各自的配体NGF、BDNF和
NT3.良性神经母细胞瘤表达TrkA和TrkC,但不表达NGF或NT3。在……里面
对比度差的转移性神经母细胞瘤表达TrkB和BDNF。基座
基于这些观察,我们提出了一个模型,在该模型中,TrkA和TrkC促进
通过诱导神经元d~(发酵)而有利于神经母细胞瘤
TrkB和BDNF的自分泌环通过促进
肿瘤生长、细胞存活和转移。为了支持这一模式,研究
已经证明TrkA和TrkC可以诱导神经元分化,TrkB
可以增加细胞存活率,刺激细胞侵袭,并且是
化学防护剂。TrkB还可增加血管内皮细胞的表达
生长因子(VEGF),提示TrkB可以诱导血管生成,这是一个关键的
参与肿瘤的增殖和转移。这笔赠款的总体目标是
获取Trk-NBL模型的体内证据。我们的实验将集中在
TrkB和与BDNF形成的自分泌/旁分泌环,结果
与TrkC和NT3相比。对于活体研究,我们将使用异种移植物
我们在实验室里开发的裸鼠模型,
大的原发肿瘤和肺、肝或骨髓的转移。目标1.我们
假设在体内,TrkB促进细胞存活、增殖和
而TrkC促进分化。我们将会比较一下
TrkB和TrkC促进细胞存活,肿瘤生长,转移,
分化,并在体内防止化疗。目标2.我们
假设BDNF/TrkB或NT3/TrkC的自分泌或旁分泌环
促进细胞存活和分化。我们将决定是否独裁
神经母细胞瘤细胞系或成纤维细胞中BDNF或NT3的表达促进
分化或生存。目的3.我们假设Trk受体调节
神经母细胞瘤中的血管生成。我们将确定TrkB和TrkC是否监管
血管内皮细胞生长因子的表达,并确定参与的信号通路。我们会
确定TrkB和TrkC是否对神经母细胞瘤诱导的缺氧有保护作用
抗血管内皮生长因子药物。通过在体内系统地比较TrkB和TrkC,这些
研究将使我们能够确定Trk-NBL模型的有效性。
项目成果
期刊论文数量(0)
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{{ truncateString('DARRELL J YAMASHIRO', 18)}}的其他基金
VEGF blockade and alternative angiogenic pathways in neuroblastoma
神经母细胞瘤中的 VEGF 阻断和替代血管生成途径
- 批准号:
8211799 - 财政年份:2008
- 资助金额:
$ 25.75万 - 项目类别:
VEGF blockade and alternative angiogenic pathways in neuroblastoma
神经母细胞瘤中的 VEGF 阻断和替代血管生成途径
- 批准号:
8016594 - 财政年份:2008
- 资助金额:
$ 25.75万 - 项目类别:
VEGF blockade and alternative angiogenic pathways in neuroblastoma
神经母细胞瘤中的 VEGF 阻断和替代血管生成途径
- 批准号:
7463093 - 财政年份:2008
- 资助金额:
$ 25.75万 - 项目类别:
VEGF blockade and alternative angiogenic pathways in neuroblastoma
神经母细胞瘤中的 VEGF 阻断和替代血管生成途径
- 批准号:
8213638 - 财政年份:2008
- 资助金额:
$ 25.75万 - 项目类别:
VEGF blockade and alternative angiogenic pathways in neuroblastoma
神经母细胞瘤中的 VEGF 阻断和替代血管生成途径
- 批准号:
7759645 - 财政年份:2008
- 资助金额:
$ 25.75万 - 项目类别:
VEGF blockade and alternative angiogenic pathways in neuroblastoma
神经母细胞瘤中的 VEGF 阻断和替代血管生成途径
- 批准号:
8136756 - 财政年份:2008
- 资助金额:
$ 25.75万 - 项目类别:
VEGF blockade and alternative angiogenic pathways in neuroblastoma
神经母细胞瘤中的 VEGF 阻断和替代血管生成途径
- 批准号:
8396624 - 财政年份:2008
- 资助金额:
$ 25.75万 - 项目类别:
VEGF blockade and alternative angiogenic pathways in neuroblastoma
神经母细胞瘤中的 VEGF 阻断和替代血管生成途径
- 批准号:
7610925 - 财政年份:2008
- 资助金额:
$ 25.75万 - 项目类别:
Role of Neurotrophin Receptors in Neuroblastoma
神经营养蛋白受体在神经母细胞瘤中的作用
- 批准号:
6514795 - 财政年份:2001
- 资助金额:
$ 25.75万 - 项目类别:
Role of Neurotrophin Receptors in Neuroblastoma
神经营养蛋白受体在神经母细胞瘤中的作用
- 批准号:
6383139 - 财政年份:2001
- 资助金额:
$ 25.75万 - 项目类别:
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