Developmental regulation of oscillatory expression

振荡表达的发育调节

基本信息

批准号：
9055984
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/9055984
关键词：
Arabidopsis Automobile Driving Beryllium Binding Biological Biological Assay Biological Pacemakers Cells Cellular biology Complex Development Developmental Biology Elements Embryo Feedback Frequencies Genetic Transcription Goals Hand 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 Radiation Regulation Regulatory Element Reporter Resolution Rhabdomyosarcoma Ribonucleoproteins Segmentation Clock Pathway Signal Pathway Signal Transduction Somites Starvation System 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 public health relevance 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.

描述（由申请人提供）：脊椎动物分段时钟是一种模型生物振荡器，它在发育中的胚胎中产生周期性模式。分段时钟控制体节发生，即脊椎动物的中胚层依次分为称为体节的节段单元的过程。分段时钟的核心是涉及她/他转录抑制子的自动抑制负反馈环，尽管“时钟和波前”模型。体细胞发生的理论已被广泛接受，但时钟调节的许多方面仍然不为人所知，而且随着我们检查体内振荡动力学的能力变得更加复杂，其他方面可能会受到挑战。直到最近几年，我们才意识到这一点。我们已经能够观察活体胚胎中的分段时钟振荡，直到最近我们才能够以单细胞分辨率做到这一点，随着我们检测快速生物振荡的能力的提高，越来越多的生物振荡器控制不同细胞的例子。反应和细胞命运决定正在被发现，强调了了解它们如何被调节的迫切需要。在本提案中，我们将重点描述振荡系统的一个很大程度上未被充分研究但至关重要的方面所需的顺式调节元件和反式作用因子。快速的转录本周转对于像脊椎动物分节时钟这样的振荡系统至关重要，在这种系统中，每一轮转录都必须伴随着一波转录本衰减来维持振荡。我们预计这项工作将广泛影响我们对许多发育环境中 RNA 周转调节的理解。 Hes1 的上调可促进横纹肌肉瘤（一种侵袭性儿童癌症）。我们对循环调节了解得越多，我们就越有可能开发出有前景的治疗人类疾病的方法或疗法，我们建议揭示控制这种振荡系统（脊椎动物分节时钟）中振荡动力学的调节机制、元件和因素，并预测。我们的工作将影响发育生物学、干细胞生物学、组织工程以及可能的癌细胞生物学等多个领域的研究。