Nostalgia in the WNT signaling pathway; fatty acids, epigenetics and leukemia

WNT信号通路中的怀旧；

基本信息

批准号：
7587938
负责人：
VINCENT E SOLLARS
金额：
$ 7万
依托单位：
MARSHALL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7587938
关键词：
Acute Myelocytic Leukemia Address Affect Animal Model Apoptosis Biological Assay Blast Phase Blood Bone Marrow Cancer and Nutrition Canola Oil Cell Culture Techniques Cell Differentiation process Cell Maintenance Chronic Myeloid Leukemia Colon Carcinoma Confocal Microscopy Corn Oil DNA Methylation Data Defect Diet Dietary Factors Dietary Fatty Acid Differentiation Inducer Disease Dominant-Negative Mutation Environment Epigenetic Process Experimental Models Exposure to Fatty Acids Fish Oils Flow Cytometry Fluorescence-Activated Cell Sorting Gene Expression Gene Expression Regulation Gene Targeting Genes Genetic Genome Head and neck structure Hematopoietic Hematopoietic stem cells Human Immunophenotyping In Vitro Incidence Laboratories Lung Malignant Neoplasms Malignant neoplasm of urinary bladder Mediating Methylation Modeling Mus Myeloid Cells Myeloid Leukemia Omega-3 Fatty Acids Omega-6 Fatty Acids Pathway interactions Premalignant Cell Prevention Prevention strategy Preventive Regulation Research Research Personnel Risk Role Smoking Stem cells Supplementation System TCF7L2 gene Testing Therapeutic Transgenic Mice Tumor Suppressor Genes Up-Regulation WNT Signaling Pathway base bcr-abl Fusion Proteins cancer risk design fatty acid metabolism granulocyte human SFRP4 protein in vitro Model in vivo leukemia macrophage mouse model promoter stem stem cell biology stem cell differentiation tumor progression uptake

项目摘要

DESCRIPTION (provided by applicant): Research indicates that epigenetic alteration of gene regulation allows survival of premalignant cells and that diet influences epigenetic regulation. By understanding dietary factors that influence epigenetic regulation of gene expression, we may be able to design effective cancer preventive strategies. This exploratory study will investigate the hypothesis that manipulation of omega 3/omega 6 fatty acid ratios can affect WNT pathway signaling through epigenetic regulation of SFRP levels in myeloid leukemias. Two experimental models will be used. To assay the connection between cancer progression, omega fatty acids, and SFRP methylation a mouse BCR-ABL chronic myelogenous leukemia (CML) blast crisis model will be used. In the first Specific Aim, we will determine the effect of high omega 3 canola oil vs. low omega 3 corn oil on the incidence of blast crisis CML. This will be correlated with the promoter methylation status of five SFRP genes using methylation specific PCR. The activity of the WNT pathway will also be determined in this animal model through flow cytometry and confocal microscopy. In Specific Aim 2, a second in vitro model of hematopoietic stem cell differentiation will be used for more manipulative studies of the effect of omega 3/ omega 6 fatty acids on differentiation and DNA methylation. The EML-clone1 cell differentiation system will be used to characterize the effect of ratios of omega 3 and omega 6 fatty acids on myeloid cell differentiation into the macrophage and granulocyte lineages. Immunophenotyping with flow cytometry will be employed to follow cellular differentiation. The studies in this proposal will test our central hypothesis in both in vivo and in vitro systems and provide preliminary evidence for preventive therapeutic approaches using dietary fatty acids. PROJECT HEALTH RELEVANCE: It has become increasingly apparent that dietary factors can affect our risk to diseases such as cancer. This proposal will draw connections between exposure to specific types of fatty acids, such as those present in fish oils, to protection from cancer. A mechanism has been proposed for the basis of this interaction and will be tested.

描述（由申请人提供）：研究表明，基因调节的表观遗传改变允许细胞的存活，饮食会影响表观遗传调节。通过了解影响基因表达表观遗传调节的饮食因素，我们可能能够设计有效的癌症预防策略。这项探索性研究将调查以下假设：对欧米茄3/欧米茄6脂肪酸比率的操纵可以通过SFRP水平的髓样白血病水平的表观遗传调节来影响Wnt途径信号传导。将使用两个实验模型。为了测定癌症进展，欧米茄脂肪酸和SFRP甲基化之间的联系，将使用小鼠BCR-ABL慢性粒细胞性白血病（CML）爆炸危机模型。在第一个特定目的中，我们将确定高欧米茄3低芥酸菜籽油与低欧米茄3玉米油对爆炸危机CML发生率的影响。使用甲基化特异性PCR，这将与五个SFRP基因的启动子甲基化状态相关。 Wnt途径的活性也将通过流式细胞仪和共聚焦显微镜在该动物模型中确定。在特定的目标2中，第二次体外造血干细胞分化模型将用于对Omega 3/ Omega 6脂肪酸对分化和DNA甲基化的影响进行更多的操纵研究。 EML-CLONE1细胞分化系统将用于表征Omega 3和Omega 6脂肪酸对骨髓细胞分化到巨噬细胞和粒细胞谱系的影响。将使用流式细胞仪进行免疫表型，以遵循细胞分化。该提案中的研究将测试我们在体内和体外系统中的中心假设，并为使用饮食脂肪酸提供预防性治疗方法的初步证据。项目健康相关性：越来越明显的是，饮食因素会影响我们对癌症等疾病的风险。该提案将在暴露于特定类型的脂肪酸（例如鱼油中存在的脂肪酸）之间与癌症进行保护。已经提出了这种相互作用的机制，并将进行测试。