Chromatin Remodeling in Cardiovascular Development

心血管发育中的染色质重塑

基本信息

批准号：
7531134
负责人：
KRYN STANKUNAS
金额：
$ 9万
依托单位：
STANFORD 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：
2008-08-01 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7531134
关键词：
ADAMTS1 gene Adverse effects Biochemical Biological Assay Biology Cardiac Jelly Cardiovascular system Cells Chromatin Chromatin Remodeling Factor Chromatin Structure Complex Congenital Abnormality Congenital Heart Defects Cultured Cells Defect Development Developmental Process Diagnosis Diagnostic Embryo Endopeptidases Event Extracellular Matrix Gene Activation Genes Genetic Transcription Goals Heart Heart Diseases Histology In Situ Hybridization Inherited Laboratories Laboratory Research Manuscripts Maps Mediating Memory Mentors Mesenchymal Methods Modification Molecular Monitor Morphogenesis Mus Muscle Muscle Cells Myocardium Neuregulins Nucleosomes Pathway interactions Pattern Peptide Hydrolases Phenotype Positioning Attribute Proteins Publications Recruitment Activity Recycling Regulation Reporter Repression Research Research Personnel Reverse Transcriptase Polymerase Chain Reaction Role Series Signal Pathway Signal Transduction Source Staging Structure Testing Thick Tissues Trans-Activators Transcript Universities Ventricular Work base cardiogenesis chromatin immunoprecipitation chromatin remodeling congenital heart disorder derepression embryo culture human ADAMTS1 protein improved independency post-doctoral training prevent programs research study response transcription factor transmission process

项目摘要

DESCRIPTION (provided by applicant): Hearts defects are the most common congenital defect and a major contributor to heart disease. Frequently, congenital heart diseases are diagnosed late in their progression, when treatments become temporary and have significant side effects. The applicant's long term goal is to establish an independent laboratory leveraging discoveries about the molecular basis of heart development into improved diagnostics and therapies for heart disease. During the remainder of his postdoctoral training at Stanford University, coursework in lab management, study of cardiovascular biology, laboratory research, and publication of manuscripts will support the applicant's transition to independency. Mentored and independent research will focus on the applicant's discovery that endocardial BAF chromatin remodeling complexes have remarkably specific roles in two heart regions. In the ventricles, the BAF complex determines the extracellular matrix required for morphogenesis of muscle cells into trabeculae by repressing transcription of a matrix protease, ADAMTS1. This regulation appears to be dynamic, as later in development ADAMTS1 expression increases to prevent excessive trabeculation. At the endocardial cushions that develop into valves, the BAF complex regulates an endocardial-to-mesenchymal transformation (EMT) that gives rise to cushion-populating cells. I hypothesize that endocardial BAF complexes establish regulatory "switches" at key loci to control developmental events in different regions of the heart. In the ventricles, I propose the BAF complex is recruited to ADAMTS1 by specific cooperating factors to induce dynamic changes in nucleosome organization to repress transcription. In the cushions, I 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 blocks EMT. These hypotheses will be pursued using two Specific Aims: 1) Determine if microenvironment changes regulate cell signaling in the ventricles. Describe cis-and Trans acting factors that recruit the BAF complex to ADAMTS1. Delineate nucleosome modifications that cooperate with the BAF complex to repress ADAMTS1. 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.

描述（由申请人提供）：心脏缺陷是最常见的先天性缺陷，也是导致心脏病的主要贡献者。通常，当治疗成为暂时并具有重大副作用时，先天性心脏病在其进展后期被诊断出来。申请人的长期目标是建立一个独立的实验室利用，将心脏发育分子基础的发现分解为改善心脏病的诊断和疗法。在他在斯坦福大学的博士后培训中，实验室管理课程，心血管生物学研究，实验室研究和手稿的发表将支持申请人过渡到独立性。受过指导和独立的研究将集中于申请人的发现，即心内膜BAF染色质重塑复合物在两个心脏区域具有非常特定的角色。在心室中，BAF复合物通过抑制基质蛋白酶的转录ADAMTS1来确定肌肉细胞形态发生所需的细胞外基质。该调节似乎是动态的，因为在发育后期的ADAMTS1表达增加以防止过度小梁。在发展为瓣膜的心内膜垫子上，BAF复合物调节心内膜转化（EMT），从而导致坐垫填充的细胞。我假设心内膜BAF复合物在关键基因座建立调节性“开关”，以控制心脏不同区域的发育事件。在心室中，我建议通过特定的合作因素招募BAF复合物来诱导核小体组织的动态变化以抑制转录。在垫子中，我假设BAF复合物调节Wnt信号传导的分泌调节剂的转录。在不存在BAF复合物的情况下，这些因素对这些因素的表现会诱导阻塞EMT的Wnt的过早和异位激活。这些假设将使用两个特定的目的来提出：1）确定微环境是否改变了心室中的细胞信号传导。描述将BAF复合物募集到ADAMTS1的顺式和反式作用因素。描述与BAF复合物合作以抑制ADAMTS1的核小体修饰。 2）确定抑制Wnt信号是否会恢复缺乏心内膜BAF复合物的胚胎中的EMT。将调节转录本的表达描述为内膜垫中BAF复合物的潜在靶标。