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基础设施的目标心脏发育的分子基础的发现改进了心脏的诊断和治疗疾病。在该奖项的 K99 部分期间，我在斯坦福大学进行博士后培训，以实现我的目标通过以下方式过渡到独立：实验室管理、学习和实验室研究课程心血管生物学、结果展示和手稿出版。这些努力最终使我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于我们发现心内膜 BAF 染色质重塑复合物在以下两个方面具有非常特殊的作用：发育中的哺乳动物心脏的区域。在心室中，BAF 复合体指定细胞外基质通过抑制基质蛋白酶的转录，将肌肉细胞形态发生为小梁所需， ADAMTSl。这种调节似乎是动态的，因为在发育后期 ADAMTS1 表达增加到防止过度小梁形成。在发育成瓣膜的心内膜垫处，BAF 复合体调节心内膜到间质转化 (EMT)，从而产生缓冲填充细胞。我们假设心内膜 BAF 复合体在关键位点建立调节“开关”以控制发育心脏不同区域的事件。在心室中，我们建议 BAF 复合体被招募到 ADAMTSl 通过特定的协同因子诱导核小体组织中的d3mamic变化来抑制转录。在缓冲层中，我们假设 BAF 复合物调节 Wnt 信号传导分泌调节因子的转录。在缺乏 BAF 复合物的情况下，这些因子的错误表达会导致过早异位激活 Wnt 可能会阻碍 EMT。这些假设将通过两个具体目标来实现：1）描述顺式和交易将 BAF 复合物募集至 ADAMTS1 的因素。描绘合作的核小体修饰与 BAF 复合物一起抑制 ADAMTS1。 2) 确定抑制 Wnt 信号传导是否可以恢复胚胎中的 EMT 缺乏心内膜 BAF 复合物。描述 Wnt 调节转录物的表达作为潜在目标心内膜垫中的 BAF 复合体。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mouse TU tagging: a chemical/genetic intersectional method for purifying cell type-specific nascent RNA.

小鼠 TU 标记：一种用于纯化细胞类型特异性新生 RNA 的化学/遗传交叉方法。

DOI：
10.1101/gad.205278.112
发表时间：
2024-09-13
期刊：
Genes & development
影响因子：
10.5
作者：
L. Gay;Michael R. Miller;P. Ventura;V. Devasthali;Z. Vue;H. Thompson;S. Temple;H. Zong;Michael D. Cleary;K. Stankunas;C. Doe
通讯作者：
C. Doe

Limited dedifferentiation provides replacement tissue during zebrafish fin regeneration.

有限的去分化在斑马鱼鳍再生过程中提供了替代组织。