Epigenetic Effect of the Microenvironment on Stem Cell Plasticity and Function
微环境对干细胞可塑性和功能的表观遗传效应
基本信息
- 批准号:7315494
- 负责人:
- 金额:$ 29.86万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2007
- 资助国家:美国
- 起止时间:2007-07-03 至 2012-05-31
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAffectBiologicalBlood VesselsCell Fate ControlCell LineCellsCharacteristicsChick EmbryoCommunicationComplexCuesDataDevelopmentDiseaseEmbryoEpigenetic ProcessGene ExpressionGene ProteinsGenesGenotypeGoalsGrantHumanImageIn SituKnowledgeLaboratoriesLimb structureMaintenanceMalignant NeoplasmsMelanoma CellMetastatic MelanomaModelingMolecularMultipotent Stem CellsMusNeural CrestNeural Crest CellNeuronsNodalNotch Signaling PathwayNude MicePathway interactionsPhenotypePlasticsPlayPopulationProcessPropertyQualifyingResearch PersonnelRoleSignal PathwaySignal TransductionStem cellsStudy modelsTestingTissuesTranslatingTransplantationTumor Cell LineUC06WA01 cell lineWA09 Cell LineWound Healingbasecancer cellcomparativeconceptdesignextracellularhuman embryonic stem cellinsightlaser capture microdissectionmelanocytemelanomaneoplastic cellnotch proteinnovelnovel therapeuticsprecursor cellprogramsreconstitutionrelating to nervous systemtumortumor progression
项目摘要
DESCRIPTION (provided by applicant): One of the most devastating diseases to manage is metastatic melanoma, where the evidence of stem cell subpopulations is starting to emerge. Comparative global gene analyses of aggressive human melanoma cell lines and tumors have revealed the expression of genes associated with multiple cellular phenotypes and precursor stem cells. These findings support the premise that aggressive melanoma cells revert to a multipotent, plastic phenotype. Key to identifying the molecular mechanisms underlying tumor cell plasticity is to elucidate the unique role the microenvironment plays in this process. Most noteworthy are the data we have generated showing the reprogramming of subpopulations (possibly the stem cells) of multipotent metastatic melanoma cells to a melanocyte-like phenotype by the embryonic microenvironment(s) of hESCs and chick neural crest-rich regions. Based on these observations, we propose to test the central hypothesis that the embryonic microenvironments associated with hESCs (Wa01. Wa09 and UC06) and chick neural crest-rich region(s) - contain informational cues with the potential to epigenetically reprogram the genotype and phenotype of human metastatic multipotent melanoma cells exposed to them. Our long term goal is to understand the biological mechanisms underlying the bi-directional communication between stem cells and their microenvironment(s) that ultimately result in cell fate determinations. Our short term goal is to identify the biological and molecular parameters associated with the epigenetic reprogramming of multipotent metastatic melanoma cells exposed to specific hESC environmental cues. Using unique, 3-D organotypic models and chick embryos, together with functional analysis, 4-D imaging, laser capture microdissection, and epigenetic analysis, we propose to: Unchanged Aim 1: Determine the epigenetic influence of the 3-D microenvironment(s) of hESCs for their potential to reprogram the genotype and phenotype of human metastatic multipotent melanoma cells. Revised Aim 2: Identify the molecular basis for the epigenetic reprogramming of the genotype and phenotype of the affected multipotent melanoma cell populations exposed to various hESC 3-D microenvironments, with particular focus on the Nodal signaling pathway. Revised Aim 3: Investigate the developmental plasticity of multipotent melanoma cell populations in an embryonic chick model - to determine the biological relevance of the Nodal signaling pathway involved in stem cell plasticity and the control of cell fate determination and reprogramming of the metastatic phenotype. Lay Summary: At the completion of these studies, we expect to gain new insights into the biological properties of human embryonic and multipotent metastatic melanoma cells with stem cell properties that could be translated for novel therapeutic applications.
描述(由申请人提供):转移性黑色素瘤是最具破坏性的疾病之一,其中干细胞亚群的证据开始出现。 对侵袭性人类黑色素瘤细胞系和肿瘤的比较性整体基因分析揭示了与多种细胞表型和前体干细胞相关的基因的表达。 这些发现支持这样的前提:侵袭性黑色素瘤细胞恢复为多能、可塑表型。 识别肿瘤细胞可塑性分子机制的关键是阐明微环境在此过程中发挥的独特作用。 最值得注意的是我们生成的数据显示,hESC 的胚胎微环境和鸡神经嵴丰富区域将多能转移性黑色素瘤细胞亚群(可能是干细胞)重编程为黑色素细胞样表型。 基于这些观察结果,我们建议测试一个中心假设,即与 hESC(Wa01、Wa09 和 UC06)和鸡神经嵴丰富区域相关的胚胎微环境包含信息线索,有可能对暴露于它们的人类转移性多能黑色素瘤细胞的基因型和表型进行表观遗传重编程。 我们的长期目标是了解干细胞与其微环境之间双向通讯的生物机制,最终决定细胞的命运。 我们的短期目标是确定与暴露于特定 hESC 环境线索的多能转移性黑色素瘤细胞的表观遗传重编程相关的生物学和分子参数。 使用独特的 3-D 器官模型和鸡胚,结合功能分析、4-D 成像、激光捕获显微切割和表观遗传分析,我们建议: 不变的目标 1:确定 hESC 3-D 微环境的表观遗传影响,了解其重编程人类转移性多能黑色素瘤细胞基因型和表型的潜力。 修订目标 2:确定暴露于各种 hESC 3-D 微环境的受影响多能黑色素瘤细胞群的基因型和表型表观遗传重编程的分子基础,特别关注 Nodal 信号通路。 修订目标 3:研究胚胎鸡模型中多能黑色素瘤细胞群的发育可塑性,以确定参与干细胞可塑性以及细胞命运决定和转移表型重编程的控制的 Nodal 信号通路的生物学相关性。 总结:在完成这些研究后,我们期望获得对具有干细胞特性的人类胚胎和多能转移性黑色素瘤细胞的生物学特性的新见解,这些特性可以转化为新的治疗应用。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
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MARY J.C. HENDRIX其他文献
MARY J.C. HENDRIX的其他文献
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{{ truncateString('MARY J.C. HENDRIX', 18)}}的其他基金
Epigenetic Effect of the Microenvironment on Stem Cell Plasticity and Function
微环境对干细胞可塑性和功能的表观遗传效应
- 批准号:
7847177 - 财政年份:2009
- 资助金额:
$ 29.86万 - 项目类别:
Epigenetic Effect of the Microenvironment on Stem Cell Plasticity and Function
微环境对干细胞可塑性和功能的表观遗传效应
- 批准号:
7631169 - 财政年份:2007
- 资助金额:
$ 29.86万 - 项目类别:
Epigenetic Effect of the Microenvironment on Stem Cell Plasticity and Function
微环境对干细胞可塑性和功能的表观遗传效应
- 批准号:
7913902 - 财政年份:2007
- 资助金额:
$ 29.86万 - 项目类别:
Epigenetic Effect of the Microenvironment on Stem Cell Plasticity and Function
微环境对干细胞可塑性和功能的表观遗传效应
- 批准号:
8070504 - 财政年份:2007
- 资助金额:
$ 29.86万 - 项目类别:
Epigenetic Effect of the Microenvironment on Stem Cell Plasticity and Function
微环境对干细胞可塑性和功能的表观遗传效应
- 批准号:
7460702 - 财政年份:2007
- 资助金额:
$ 29.86万 - 项目类别:
Epigenetic Effect of the Microenvironment on Stem Cell Plasticity and Function
微环境对干细胞可塑性和功能的表观遗传效应
- 批准号:
7860642 - 财政年份:2007
- 资助金额:
$ 29.86万 - 项目类别:
Epigenetic Effect of the Microenvironment on Stem Cell Plasticity and Function
微环境对干细胞可塑性和功能的表观遗传效应
- 批准号:
7080224 - 财政年份:2005
- 资助金额:
$ 29.86万 - 项目类别:
PROSTATIC VASCULOGENIC MIMICRY: A NEW METASTATIC PATHWAY
前列腺血管生成拟态:一种新的转移途径
- 批准号:
6474760 - 财政年份:2000
- 资助金额:
$ 29.86万 - 项目类别:
PROSTATIC VASCULOGENIC MIMICRY: A NEW METASTATIC PATHWAY
前列腺血管生成拟态:一种新的转移途径
- 批准号:
6514729 - 财政年份:2000
- 资助金额:
$ 29.86万 - 项目类别:
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