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（由应用程序提供）：脊椎动物分割时钟是一种模型生物学振荡器，在开发胚胎时会产生周期性模式。分割时钟控制了体体发生，脊椎动物的中胚层依次将其依次分为称为Somites的分段单元。分割时钟的核心是她/hes转录表示的自动抑制作用反馈回路。尽管人们广泛接受了体体发生的“时钟和波前”模型，但时钟调节的一些方面仍然尚不清楚，而且随着我们检查体内检查振荡动力学的能力，可能会受到挑战的其他方面。直到最近几年，我们才能够观察分段时钟在活胚胎中的振荡，而最近才能通过单细胞分辨率来做到这一点。随着我们检测快速生物振荡的能力，正在发现越来越多的控制科学细胞反应和细胞脂肪决策的生物振荡的例子，这强调了了解如何调节它们的关键需求。在此提案中，我们将集中精力表征在很大程度上理解但至关重要的振荡系统所需的CIS调节元件和跨性别因素（循环转录本衰减）的关键方面。营业额在诸如脊椎动物分割时钟之类的振荡系统中至关重要，在脊椎动物分段时钟，必须随后每轮转录浪潮腐烂以维持振荡。我们已经有一个掌握的因素PNRC2，该因素将在很大程度上支持鉴定自环转录本“衰减复合物”。我们预计，这项工作广泛地影响了我们对许多发育环境中对RNA转移的调节的理解。快速分子振荡器不仅对于在发育过程中产生节段模式，而且对于促进神经干细胞中的异质反应以及将胚胎干细胞偏向不同的细胞命运而言。此外，HES1上调促进了横纹肌肉瘤，这是一种侵略性的儿童癌。这，我们越了解环状调节，我们就越有可能为人类疾病开发有希望的治疗或治疗。我们建议揭示控制一个振荡系统，脊椎动物分割时钟中控制振荡动态的监管机制，元素和因素，并预测我们的工作将影响像潜水员一样的研究研究，如发育生物学，干细胞生物学，组织工程，组织工程以及可能的癌细胞生物学。