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Ribosomes and Regeneration: Defining the Role of Protein Synthesis in Tissue Development, Homeostasis and Repair.

核糖体和再生：定义蛋白质合成在组织发育、稳态和修复中的作用。

基本信息

批准号：
9805445
负责人：
Olena Zhulyn
金额：
$ 11.19万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9805445
关键词：
Acute Address Advisory Committees Affect Ambystoma Area Cartilage Cell Differentiation process Cell Survival Cells Chondrocytes Code Complement Complex Coupled Development Digit structure Disease Embryonic Development Ensure FRAP1 gene Gatekeeping Gene Expression Gene Expression Regulation Genes Genetic Genetic Models Genetic Transcription Glycobiology Goals Health Heterogeneity Homeostasis Human Immunoprecipitation In Vitro Injury Investigation Label Limb structure Mammals Mass Spectrum Analysis Measurement Mediating Messenger RNA Methods Modeling Molecular Mus Natural regeneration Organoids Output Pathway interactions Phase Play Post-Translational Protein Processing Process Production Protein Biosynthesis Proteins Proteome Regenerative Medicine Regulation Research Research Personnel Ribosomal Proteins Ribosomes Role Salamander Signal Pathway Signal Transduction Site Spinal Cord Stress System Testing Therapeutic Therapeutic Intervention Time Tissue-Specific Gene Expression Tissues Trans-Activators Transcript Translating Translational Regulation Translations Universities Up-Regulation Variant Vertebrates Work Wound Healing articular cartilage base cell type collaborative environment gene product in vivo in vivo Model knock-down limb amputation limb regeneration mTOR Signaling Pathway multidisciplinary novel polysome profiling regenerative repaired response small molecule inhibitor stem cell differentiation tissue degeneration tissue regeneration tissue repair transcriptome sequencing wound closure

项目摘要

PROJECT SUMMARY/ABSTRACT Translation has emerged as a new and important layer of regulation at the last step in the journey from gene to gene product. This regulation is conferred in part through the activity of specialized ribosomes which vary in their complement of ribosomal proteins and have the capacity to selectively translate specific subsets of mRNAs. While this mechanism may offer cells an unparalleled ability to rapidly adjust protein output, the extent and impact of ribosome-mediated translational regulation has not yet been addressed in terminally differentiated cells and tissues or at the organismal level. My preliminary studies demonstrate that translational regulation may be of particular importance in promoting tissue regeneration in the axolotl - a species of highly regenerative salamander. Using axolotl limb amputation as a model, I demonstrate that unlike in mammals, severe injury in this species triggers a rapid translational response which selectively targets translation of ribosomal proteins. In this proposal I examine the role of regulated protein synthesis in the axolotl and mouse; I establish the role of specialized ribosomes in the process of axolotl limb regeneration and I extend the scope of this research to murine chondrocytes and a novel human cartilage organoid system, in order to define the role of specialized ribosomes in the development, regeneration and repair of vertebrate tissues. The long-term goal of this work is to utilize in vitro and in vivo models, including micromass murine chondrocyte culture and human cartilage organoids, genetic modeling in mice and regeneration modeling in axolotls, coupled with state-of-the-art mass spectrometry and ribosome/polysome profiling methods to define the role of ribosome-mediated translational regulation in tissue development and disease and to identify new genes and factors with therapeutic potential in tissue regeneration, with a particular emphasis on cartilage health. The research proposed in this application will be carried out within the highly collaborative environment of Stanford University and supported by a multidisciplinary advisory committee with expertise in translation control, glycobiology, axolotl regeneration and stem cell differentiation. Upon completion of the K99 phase, the candidate’s goals are to continue this work as an independent investigator in an academic research setting.

项目总结/文摘