THE ROLE OF CSF-1 MEDIATED MACROPHAGE CHEMOTAXIS IN CARCINOMA CELL INVASION
CSF-1介导的巨噬细胞趋化作用在癌细胞侵袭中的作用
基本信息
- 批准号:7569444
- 负责人:
- 金额:$ 30.63万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2006
- 资助国家:美国
- 起止时间:2006-02-01 至 2011-01-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Tumor-associated macrophages (TAM), which are present in large numbers in many tumors, appear to play
an important role in promoting the progression of solid tumors to an invasive, metastatic phenotype. It has
been shown recently that TAM participate in a paracrine loop with carcinoma cells such that the CSF-1-
producing carcinoma cells and the EGF-secreting macrophages (MD) interact to promote mutual chemotaxis
leading to invasion and extravasation of carcinoma cells. In MDs, PI 3-kinase, Cdc42 and WASP (Wiskott-
Aldrich syndrome protein) are required for migrating cells to detect the source of a chemoattractant. It has
been speculated that amplification of the extracellular gradient occurs through an intracellular positive
feedback loop involving PI 3-kinase, Rho GTPases and actin assembly. The precise function of WASP in
gradient detection is not known. Based on preliminary data, WASP activity is required for CSF-1 induced
actin polymerization in MDs which may contribute to the reinforcement of the positive feedback loop in CSF-
1 gradient detection (chemotactic sensing) leading to efficient chemotaxis. In the first Specific Aim, the role
of PI3K and Cdc42 in the activation of WASP will be determined using PI3K inhibitors, CSF-1R mutations
that lack PI3K activation, and by reducing endogenous levels of Cdc42 using siRNA technology. The
mechanisms of WASP activation will be examined through mutational analysis of a fluorescence resonance
energy transfer (FRET) based WASP biosensor. In Specific Aim 2, the role of WASP mediated actin
polymerization in chemotactic sensing will be determined. The role of WASP in the localization of PI3K and
Cdc42 in chemotactic sensing will be determined by live cell imaging. In addition, we will perform
biochemical isolation of CSF-1 elicited pseudopods from wild-type and WASP-deficient macrophages in
order to identify potential WASP interacting proteins. In Specific Aim 3 The effect of WASP on polarization
and movement of MD and carcinoma cells will be examined using an in vitro assay that reconstitutes the
paracrine interaction between MD and tumor cells.
Relevance: Understanding how MDs migrate into a tumor site and their interaction with carcinoma cells, is
an important area of investigation in cancer biology. Since WASP is specifically required for MD chemotaxis
it may represent a novel target and may lead to new therapies to prevent metastasis
在许多肿瘤中大量存在的肿瘤相关巨噬细胞(TAM)似乎在玩耍
在促进实体瘤向侵入性转移表型的进展方面的重要作用。它有
最近显示,TAM参与了带有癌细胞的旁分泌环,因此CSF-1--
产生癌细胞和EGF分泌巨噬细胞(MD)相互作用以促进相互趋化性
导致癌细胞的侵袭和渗出。在MDS中,PI 3-激酶,Cdc42和黄蜂(Wiskott-
Aldrich综合征蛋白是迁移细胞需要检测趋化剂来源所必需的。它有
被推测,细胞外梯度的扩增是通过细胞内阳性发生的
反馈回路涉及PI 3-激酶,Rho GTPases和肌动蛋白组件。黄蜂的精确功能
梯度检测尚不清楚。基于初步数据,CSF-1诱导的WASP活动需要
MDS中的肌动蛋白聚合可能有助于加强CSF-
1梯度检测(趋化感应)导致有效的趋化性。在第一个特定目标中,角色
在黄蜂激活中PI3K和CDC42的激活中,将使用PI3K抑制剂确定CSF-1R突变
缺乏PI3K激活,并且通过使用siRNA技术降低内源性CDC42。这
黄蜂激活的机制将通过突变分析荧光共振
基于能量转移(FRET)WASP生物传感器。在特定的目标2中,黄蜂介导的肌动蛋白的作用
将确定趋化感应中的聚合。黄蜂在PI3K定位中的作用
趋化感应中的Cdc42将由活细胞成像确定。此外,我们将表演
CSF-1的生化分离从野生型和黄蜂缺乏巨噬细胞引起的假脚架中
为了识别潜在的黄蜂相互作用蛋白。在特定的目标3中,黄蜂对极化的影响
MD和癌细胞的运动将使用重构的体外测定法检查
MD和肿瘤细胞之间的旁分泌相互作用。
相关性:了解MDS如何迁移到肿瘤部位及其与癌细胞的相互作用是
癌症生物学研究的重要领域。由于MD趋化性是特别需要黄蜂的
它可能代表一个新颖的目标,并可能导致新的疗法以防止转移
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

暂无数据
数据更新时间:2024-06-01
Dianne Cox的其他基金
2017 Phagocytes Gordon Research Conference and Gordon Research Seminar
2017吞噬细胞戈登研究大会暨戈登研究研讨会
- 批准号:93259189325918
- 财政年份:2017
- 资助金额:$ 30.63万$ 30.63万
- 项目类别:
THE ROLE OF CSF-1 MEDIATED MACROPHAGE CHEMOTAXIS IN CARCINOMA CELL INVASION
CSF-1介导的巨噬细胞趋化作用在癌细胞侵袭中的作用
- 批准号:77638747763874
- 财政年份:2006
- 资助金额:$ 30.63万$ 30.63万
- 项目类别:
Pososome Regulated Monocyte/Macrophage Tissue Infiltration
脂质体调节单核细胞/巨噬细胞组织浸润
- 批准号:84647318464731
- 财政年份:2006
- 资助金额:$ 30.63万$ 30.63万
- 项目类别:
Pososome Regulated Monocyte/Macrophage Tissue Infiltration
脂质体调节单核细胞/巨噬细胞组织浸润
- 批准号:86563548656354
- 财政年份:2006
- 资助金额:$ 30.63万$ 30.63万
- 项目类别:
THE ROLE OF CSF-1 MEDIATED MACROPHAGE CHEMOTAXIS IN CARCINOMA CELL INVASION
CSF-1介导的巨噬细胞趋化作用在癌细胞侵袭中的作用
- 批准号:71719247171924
- 财政年份:2006
- 资助金额:$ 30.63万$ 30.63万
- 项目类别:
Pososome Regulated Monocyte/Macrophage Tissue Infiltration
脂质体调节单核细胞/巨噬细胞组织浸润
- 批准号:81875538187553
- 财政年份:2006
- 资助金额:$ 30.63万$ 30.63万
- 项目类别:
THE ROLE OF CSF-1 MEDIATED MACROPHAGE CHEMOTAXIS IN CARCINOMA CELL INVASION
CSF-1介导的巨噬细胞趋化作用在癌细胞侵袭中的作用
- 批准号:70357017035701
- 财政年份:2006
- 资助金额:$ 30.63万$ 30.63万
- 项目类别:
THE ROLE OF CSF-1 MEDIATED MACROPHAGE CHEMOTAXIS IN CARCINOMA CELL INVASION
CSF-1介导的巨噬细胞趋化作用在癌细胞侵袭中的作用
- 批准号:73454067345406
- 财政年份:2006
- 资助金额:$ 30.63万$ 30.63万
- 项目类别:
Pososome Regulated Monocyte/Macrophage Tissue Infiltration
脂质体调节单核细胞/巨噬细胞组织浸润
- 批准号:83100178310017
- 财政年份:2006
- 资助金额:$ 30.63万$ 30.63万
- 项目类别:
Nck and Crk in VEGF-Induced Endothelial Cells Migration
Nck 和 Crk 在 VEGF 诱导的内皮细胞迁移中的作用
- 批准号:75546537554653
- 财政年份:2005
- 资助金额:$ 30.63万$ 30.63万
- 项目类别:
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