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，也是心脏病的主要原因。先天性心脏病通常在病情进展后期才被诊断出来，此时治疗变得暂时且具有显着的副作用。申请人的长期目标是建立一个独立的实验室，利用心脏发育的分子基础的发现来改进心脏病的诊断和治疗。在斯坦福大学剩余的博士后培训期间，实验室管理、心血管生物学研究、实验室研究和手稿出版等课程将支持申请人向独立的过渡。指导和独立研究将重点关注申请人的发现，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殊的作用。在心室中，BAF 复合物通过抑制基质蛋白酶 ADAMTS1 的转录来决定肌肉细胞形态发生为小梁所需的细胞外基质。这种调节似乎是动态的，因为在发育后期 ADAMTS1 表达会增加以防止过度的小梁形成。在发育成瓣膜的心内膜垫处，BAF 复合体调节心内膜到间质的转化 (EMT)，从而产生垫填充细胞。我假设心内膜 BAF 复合体在关键位点建立调节“开关”，以控制心脏不同区域的发育事件。在心室中，我建议 BAF 复合物通过特定的协同因子被招募到 ADAMTS1，以诱导核小体组织的动态变化，从而抑制转录。在缓冲垫中，我假设 BAF 复合物调节 Wnt 信号传导分泌调节因子的转录。在 BAF 复合物缺失的情况下，这些因子的错误表达会诱导 Wnt 过早异位激活，从而阻断 EMT。这些假设将通过两个具体目标来实现：1）确定微环境变化是否调节心室中的细胞信号传导。描述将 BAF 复合物招募到 ADAMTS1 的顺式和反式作用因子。描绘与 BAF 复合物配合抑制 ADAMTS1 的核小体修饰。 2) 确定抑制 Wnt 信号传导是否可以恢复缺乏心内膜 BAF 复合物的胚胎中的 EMT。描述 Wnt 调节转录物的表达作为心内膜垫中 BAF 复合物的潜在靶标。