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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.

这个项目将支持我的独立实验室的建立及其撬动基础的目标