RAF KINASE AND EPIGENETIC REGULATION OF FETAL VASCULAR DEVELOPMENT

RAF 激酶和胎儿血管发育的表观遗传调控

基本信息

批准号：
9134923
负责人：
Ravi Goyal
金额：
$ 39.5万
依托单位：
LOMA LINDA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-11 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9134923
关键词：
Adipocytes Adult Apoptosis Apoptotic Arteries BRAF gene Basic Science Binding Biological Assay Blood Vessels CD34 gene Cell Death Cell Survival Cells Cerebral Palsy Clinical Collagen DNA DNA Methylation Data Data Reporting Defect Development Dioxygenases Disease Embryo Endothelial Cells Epigenetic Process Family Fetal Development Fibroblasts Gene Expression Gene Expression Regulation Genes Genetic Genetic Transcription Growth Health Hemangioma Hypermethylation Immunoprecipitation Ions Knockout Mice Lead Life MAP Kinase Gene MAPK3 gene MCAM gene Malignant Neoplasms Mediating Mediator of activation protein Mesenchymal Stem Cells Methylation Mus Myocardial Infarction Neonatal Nuclear Translocation Osteocytes Pathogenesis Pathway interactions Phosphotransferases Play Population Pregnancy Process Protein Binding Protein Isoforms Protein Kinase C Proteins Proto-Oncogene Proteins B-raf Regenerative Medicine Regulation Reporter Genes Role Signal Transduction Smooth Muscle Myocytes Stat3 protein Stem cells Stroke Structure TP53 gene Testing Transcript Transferase Tube Vascular Diseases Vascular Proliferation Vascular System Vascular blood supply Woman Work Wound Healing angiogenesis base blood vessel development crosslink enzyme activity epigenetic regulation fetal fetal blood gain of function genome wide methylation innovation loss of function member new therapeutic target novel organ growth pluripotency promoter raf Kinases reproductive research study response therapeutic target vasculogenesis

Adipocytes Adult Apoptosis Apoptotic Arteries BRAF gene Basic Science Binding Biological Assay Blood Vessels CD34 gene Cell Death Cell Survival Cells Cerebral Palsy Clinical Collagen DNA DNA Methylation Data Data Reporting Defect Development Dioxygenases Disease Embryo Endothelial Cells Epigenetic Process Family Fetal Development Fibroblasts Gene Expression Gene Expression Regulation Genes Genetic Genetic Transcription Growth Health Hemangioma Hypermethylation Immunoprecipitation Ions Knockout Mice Lead Life MAP Kinase Gene MAPK3 gene MCAM gene Malignant Neoplasms Mediating Mediator of activation protein Mesenchymal Stem Cells Methylation Mus Myocardial Infarction Neonatal Nuclear Translocation Osteocytes Pathogenesis Pathway interactions Phosphotransferases Play Population Pregnancy Process Protein Binding Protein Isoforms Protein Kinase C Proteins Proto-Oncogene Proteins B-raf Regenerative Medicine Regulation Reporter Genes Role Signal Transduction Smooth Muscle Myocytes Stat3 protein Stem cells Stroke Structure TP53 gene Testing Transcript Transferase Tube Vascular Diseases Vascular Proliferation Vascular System Vascular blood supply Woman Work Wound Healing angiogenesis base blood vessel development crosslink enzyme activity epigenetic regulation fetal fetal blood gain of function genome wide methylation innovation loss of function member new therapeutic target novel organ growth pluripotency promoter raf Kinases reproductive research study response therapeutic target vasculogenesis

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项目摘要

DESCRIPTION (provided by applicant): Raf Kinase and Epigenetic Regulation of Fetal Vascular Development. Project Summary Development of the vasculature is a dynamic process that relies on the coordinated expression of numerous genes. The factors that regulate gene expression during blood vessel development are not well defined, however. Our preliminary data and reports from others of impaired vascular development in B-Raf knockout mice have elucidated the significance of this pathway in the developing vasculature. Importantly, downstream mechanism(s) through which B-Raf regulates vascular development are not known. Based on our preliminary data, we propose that B-Raf kinases via Protein Kinase C (PKC), Signal Transducer and Activator of Transcription 3 (STAT3) and p53 regulate DNA methyl Transferase (DNMT) and Ten-Eleven Translocation Methylcytosine Dioxygenase (TET) gene expression and activities. The altered activities of DNMT and TET lead to changes in promoter DNA methylation resulting in altered expression of genes regulating apoptosis such as Bcl2. These pathways play a crucial role in fetal vascular development. In this project, we will test the hypothesis that B-Raf hypomethylates the Bcl2 promoter to regulate fetal vascular stem cell survival. In the three Specific Aims, we will examine the (1) downstream mediators of B-Raf such as PKC, STAT3, and p53 (2) B-Raf-mediated regulation of DNMT and TET expression and activity, and (3) B-Raf-mediated regulation of promoter DNA methylation of the antiapoptotic gene Bcl2 via DNMT and TET. These studies are highly innovative and significant. Kinase-mediated regulation of epigenetic phenomenon such as DNA methylation is not well studied and is of fundamental importance from a basic science perspective. Moreover, pathways regulating fetal VSC apoptosis are involved in the pathogenesis of several fetal and neonatal disorders such as growth restriction, cerebral palsy, hemangioma, etc. From a clinical perspective, these studies will provide several therapeutic targets to regulate angiogenesis and vascular proliferation in many conditions from organ growth and wound healing to disorders such as myocardial infarction, cerebrovascular accident (stroke), and fetal development in general.

描述（适用提供）：胎儿血管发育的RAF激酶和表观遗传调节。脉管系统的项目摘要开发是一个动态过程，依赖于许多基因的协调表达。但是，调节血管发育过程中基因表达的因素尚未很好地定义。我们的初步数据和其他有关B-RAF敲除小鼠血管发育受损的报告，重要的是，重要的是下游机制，B-RAF调节血管发育尚不清楚。根据我们的初步数据，我们提出了通过蛋白激酶C（PKC），转录3（STAT3）和p53的B-RAF激酶通过蛋白激酶C（PKC），信号传感器和激活剂调节DNA甲基转移酶（DNMT）和十倍易位的甲基胞三糖苷dioxygengenase（Tet）基因表达和活性。 DNMT和TET的活性改变导致启动子DNA甲基化的变化，导致基因调节凋亡（例如BCL2）的表达改变。这些途径在胎儿血管发育中起着至关重要的作用。在该项目中，我们将检验以下假设：B-RAF低甲基甲基甲基启动子调节胎儿血管干细胞的存活。在三个具体目标中，我们将研究B-RAF的（1）下游介质，例如PKC，STAT3和P53（2）B-RAF介导的DNMT和TET表达和活性的调节，以及（3）B-RAF介导的抗蛋白基因BCL 2NMT和TET的抗蛋白基因BCL 2的启动子DNA甲基化的调节。这些研究具有很高的创新性和重要意义。激酶介导的表观遗传现象（例如DNA甲基化）的调节尚未很好地研究，并且从基础科学的角度来看至关重要。此外，从临床角度，这些研究将提供多种治疗靶点，从而在许多治疗范围内，这些研究将提供多种治疗靶点，从而在许多情况下，在许多治疗状态下，在许多治疗状态下，这些研究将提供多种治疗靶点，例如，在许多治疗疾病中，造成了多种疾病的疾病，途径将提供多种治疗靶点，从而，这些研究将提供几种胎儿和新生儿疾病（例如生长限制，脑瘫，血管瘤等）的多种胎儿和新生儿疾病的发病机理。（中风）和胎儿发育。