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Developmental regulation of oscillatory expression

振荡表达的发育调节

基本信息

批准号：
9146394
负责人：
Sharon L Amacher
金额：
$ 31.57万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-18 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9146394
关键词：
Arabidopsis Automobile Driving Beryllium Binding Biological Biological Assay Biological Pacemakers Cells Cellular biology Complex Development Developmental Biology Elements Embryo Feedback Frequencies Gamma Rays Genetic Transcription Goals Hand Health Histocompatibility Testing Hour Indium Individual Lateral Life Malignant Childhood Neoplasm Mesoderm Mesoderm Cell Metabolic Methods Modeling Molecular Molting Nuclear Pattern Physiologic pulse Plant Roots Post-Transcriptional Regulation Process Proteins RNA Regulation Regulatory Element Reporter Resolution Rhabdomyosarcoma Ribonucleoproteins Segmentation Clock Pathway Signal Pathway Signal Transduction Somites Starvation System TP53 gene Therapeutic Tissue Engineering Trans-Activators Transcript Transcription Repressor/Corepressor Transcriptional Regulation Untranslated Regions Up-Regulation Vertebrates Work Yeasts Zebrafish biological systems cancer cell cell type cytokine embryonic stem cell human disease improved in vivo nerve stem cell response somitogenesis stem cell biology transcription factor

项目摘要

DESCRIPTION (provided by applicant): The vertebrate segmentation clock is a model biological oscillator that generates periodic pattern in developing embryos. The segmentation clock controls somitogenesis, the process by which the mesoderm of the vertebrate animal is sequentially divided into segmental units called somites. At the core of the segmentation clock is an auto-inhibitory negative feedback loop involving her/Hes transcriptional repressors. Although the `clock and wave front' model of somitogenesis is widely accepted, there are still many aspects of clock regulation that are not understood, and yet other aspects that may be challenged as our ability to examine oscillation dynamics in vivo becomes more sophisticated. It is only over the last few years that we have been able to watch the segmentation clock oscillate in living embryos and only very recently that have we been able to do so with single cell resolution. As our ability to detect rapid biological oscillations improves, more and more examples of biological oscillators controlling diverse cellular responses and cell fate decisions are being discovered, underscoring a critical need to understand how they are regulated. In this proposal, we will focus on characterizing the cis regulatory elements and trans-acting factors required for a largely understudied but critical aspect of oscillatory systems - that of cyclic transcript decay. Rapid transcript turnover is critical in oscillatory systems like the vertebrate segmentation clock, where every round of transcription must be followed by a wave of transcript decay to sustain oscillations. We already have one factor in hand, Pnrc2, which will greatly facilitate the identification of a cyclic transcript "decay complex". We anticipate that this work ill broadly impact our understanding of regulation of RNA turnover in many developmental contexts. Rapid molecular oscillators are not only important for generating segmental pattern during development, but also for promoting heterogeneous responses in neural stem cells, and for biasing embryonic stem cells toward different cell fates. Additionally, Hes1 upregulation promotes rhabdomyosarcoma, an aggressive childhood cancer. Thus, the more we understand cyclic regulation, the more likely we are to develop promising treatments or therapeutics for human disease. We propose to uncover regulatory mechanisms, elements, and factors that control oscillation dynamics in one such oscillatory system, the vertebrate segmentation clock, and anticipate that our work will impact studies in fields as diverse as developmental biology, stem cell biology, tissue engineering, and possibly cancer cell biology.