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Chromatin Remodeling in Cardiovascular Development

心血管发育中的染色质重塑

基本信息

批准号：
8310027
负责人：
KRYN STANKUNAS
金额：
$ 24.9万
依托单位：
UNIVERSITY OF OREGON
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-02 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8310027
关键词：
ADAMTS1 gene Award Binding Biochemical Biological Assay Biology Candidate Disease Gene Cardiac Jelly Cardiovascular system Cells Chromatin Chromatin Remodeling Factor Chromatin Structure Complex Congenital Abnormality Congenital Heart Defects Defect Development Developmental Process Diagnostic Embryo Event Extracellular Matrix Faculty Gene Activation Genes Genetic Genetic Transcription Goals Heart Heart Diseases Human In Situ Hybridization Inherited Laboratories Laboratory Research Manuscripts Mediating Medical Memory Mesenchymal Modification Molecular Morphogenesis Mus Muscle Muscle Cells Myocardium Nucleosomes Oregon Pathway interactions Pattern Peptide Hydrolases Phenotype Positioning Attribute Proteins Publications Recruitment Activity Recycling Regulation Repression Research Reverse Transcriptase Polymerase Chain Reaction Role Series Signal Pathway Signal Transduction Specific qualifier value Staging Testing Thick Tissues Transact Transcript Universities Work base cardiogenesis chromatin remodeling derepression embryo culture improved independency mutant novel post-doctoral training premature prevent programs research study response transcription factor

项目摘要

This project will support the establishment of my independent laboratory and its goals of leveraging basic discoveries on the molecular basis of heart development into improved diagnostics and therapies for heart disease. During the K99 portion of this award, I pursued postdoctoral training at Stanford University towards my transition to independency by: coursework in lab management, studies and laboratory research in cardiovascular biology, presentation of results, and publication of manuscripts. These efforts culminated in my acceptance of a tenure-track faculty position at the University of Oregon. There, my lab's research will focus on our discovery that endocardial BAF chromatin remodeling complexes have remarkably specific roles in two regions of the developing mammalian heart. In the ventricles, the BAF complex specifies the extracellular matrix required for morphogenesis of muscle cells into trabeculae by repressing transcription of a matrix protease, ADAMTSl. This regulation appears to be dynamic, as later in development ADAMTSl expression increases to prevent excessive trabeculation. At the endocardial cushions that develop into valves, the BAF complex regulates an endocardial-to-mesench3mtial transformation (EMT) that gives rise to cushion-populating cells. We hypothesize that endocardial BAF complexes establish regulatory "switches" at key loci to control developmental events in different regions of the heart. In the ventricles, we propose the BAF complex is recruited to ADAMTSl by specific cooperating factors to induce d3mamic changes in nucleosome organization to repress transcription. In the cushions, we hypothesize the BAF complex regulates transcription of secreted regulators of Wnt signaling. Misexpression of these factors in the absence of the BAF complex induces a premature and ectopic activation of Wnt that may block EMT. These hypotheses will be pursued using two Specific Aims: 1) Describe cis- and transacting factors that recruit the BAF complex to ADAMTSl. Delineate nucleosome modifications that cooperate with the BAF complex to repress ADAMTSl. 2) Determine if inhibiting Wnt signaling restores EMT in embryos lacking endocardial BAF complexes. Describe the expression of Wnt regulating transcripts as potential targets of the BAF complex in endocardial cushions.

该项目将支持我的独立实验室的建立及其利用Basic 心脏发育的分子基础上的发现改进了心脏的诊断和治疗疾病。在该奖项的K99部分，我在斯坦福大学继续博士后培训，以获得我的过渡到独立：实验室管理、研究和实验室研究方面的课程心血管生物学、成果介绍和手稿出版。这些努力最终导致了我的接受俄勒冈大学终身教职。在那里，我的实验室的研究将集中在我们发现心内膜BAF染色质重塑复合体在两种情况下具有显著的特异性作用发育中的哺乳动物心脏的区域。在脑室，BAF复合体指定细胞外基质肌肉细胞通过抑制基质蛋白酶的转录而形成小梁所必需的， ADAMTSl.这种调节似乎是动态的，因为在发育后期，ADAMTS1的表达增加到防止过度的骨小梁。在发展成瓣膜的心内膜垫上，BAF复合体调节心内膜到间质的转化(EMT)，从而产生垫状填充细胞。我们心内膜BAF复合体在控制发育的关键位点建立调控“开关”的假设心脏不同区域的事件。在脑室，我们建议BAF复合体被招募到ADAMTSl 通过特定的协同因子诱导d3核小体组织的变化来抑制转录。在垫子上，我们假设BAF复合体调节Wnt信号分泌调节因子的转录。在没有BAF复合体的情况下，这些因子的错误表达导致过早和异位激活 WNT可能会阻止EMT。这些假设将通过两个具体目标来实现：1)描述顺应性和交易性将BAF复合体招募到ADAMTS1的因素。勾勒出相互配合的核小体修饰与BAF复合体一起抑制ADAMTS1。2)确定抑制Wnt信号是否能恢复胚胎的EMT 缺乏心内膜BAF复合体。描述作为潜在靶点的Wnt调控转录本的表达心内膜垫内的BAF复合体。