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Gravitational Regulation of Osteoblast Genomics and Metabolism

成骨细胞基因组和代谢的重力调节

基本信息

批准号：
8154099
负责人：
BRUCE E HAMMER
金额：
$ 23.97万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8154099
关键词：
Address Affect American Animals Apoptosis Astronauts Back Beds Biochemical Biological Biological Assay Biological Markers Biological Preservation Bioreactors Bone remodeling Cell Culture System Cell Culture Techniques Cell Differentiation process Cells Cellular Morphology Certification Cues Development Differentiation Antigens Disease Drug Design Environment Enzyme-Linked Immunosorbent Assay Evaluation Force of Gravity Fracture Gene Expression Genes Genomics Habitats Homeostasis Incubators Individual International Logistics MAP Kinase Gene MAPK Signaling Pathway Pathway Magnetism Maintenance Measurable Measures Mechanical Stress Metabolism Methods Metric Microarray Analysis Microgravity Minnesota Mission Molecular NFKB Signaling Pathway NMR Spectroscopy Nutrient Ocular orbit Orbital Simulations Osteoblasts Osteoclasts Osteogenesis Osteonectin Osteopenia Osteoporosis Outcome Pathway interactions Patients Performance Phase Physical therapy Physiology Proteomics Protocols documentation Regulation Research Research Personnel Reverse Transcriptase Polymerase Chain Reaction Role Running Sampling Screening procedure Signal Pathway Signaling Pathway Gene Simulate Stress TNFSF11 gene Techniques Technology Testing Tissue-Specific Gene Expression Training United States National Aeronautics and Space Administration United States National Institutes of Health Universities Water Weight-Bearing state Western Blotting Work base bone bone cell bone loss bone mass cell growth experience falls instrumentation metabolomics older patient osteopontin protein expression research study response skeletal tissue tool

项目摘要

DESCRIPTION (provided by applicant): The role of gravity in the development and maintenance of bone on earth is controversial. Our current understanding is that gravitational unloading of bone results in bone loss (osteopenia) which typically progresses to osteoporosis and ultimately bone fracture. This is a significant problem that bed- ridden patients and the elderly experience. Astronauts in orbit experience significant osteopenia of approximately 1% to 3% of bone loss per month, which is equivalent to a year of bone loss for osteoporotic individuals on earth. Understanding bone response to varying levels of gravitational force is critical toward developing rational approaches in drug design or physical therapy toward mitigating osteopenia. Presently, the only means of exposing bone to a long-term lack of gravitational force is through orbital free fall aboard the ISS. These studies are expensive and logistically difficult to do aboard the ISS. An ideal method of study gravitational regulation of bone dynamics is to have a ground-based method to remove or reduce the gravitational force on bone. Creating an environment that amplifies the rate of bone loss will give us a tool to accelerate our understanding of the underlying genomic, proteomic and metabolomic mechanisms. The proposed study seeks to determine if ground-based magnetic levitation is a suitable simulation of orbital free fall for cell culture studies. Studying a cell culture rather than an entire animal allows for highly controlled and reproducible experiments. We plan to grow MC3T3 osteoblastic and primary osteoclastic cells in a bioreactor compatible with our ground-based levitation magnet and the ISS space-based microgravity environment. Our unique levitation magnet integrates a 37 C incubator integrated into the magnet bore allowing levitation for several weeks. The implementation partner for experiments aboard the ISS is BioServe Space Technologies in Boulder, CO. BioServe has a two-decade record of accomplishment of working with NASA on delivering biological experiments to and from low-earth orbit. Osteoblasts and osteoclasts flown on previous orbital missions show evidence that microgravity affects cell differentiation and gene expression. The metrics for the proposed study include cell morphology studies, microarray analysis to measure differential gene expression, ELISA and RT-PCR to identify markers of osteoblast and osteoclast differentiation, metabolomics, via H-1 NMR spectroscopy and quantification of MAPK, Twsg1 and NF-kB signaling pathways. With this suite of assays, we will determine similarities and differences in a number of metabolites and biomarkers for simulated microgravity and ISS microgravity environments. This project will help identify mechanism(s) and pathways that can be addressed to mitigate bone loss on earth. PUBLIC HEALTH RELEVANCE: Understanding bone response to varying levels of gravitational force is critical toward developing rational approaches in drug design or physical therapy toward mitigating bone loss and debilitating bone fracture. The proposed study seeks to determine if ground-based magnetic levitation is a suitable simulation of orbital free fall for cell culture studies.

描述（由申请人提供）：重力在地球上骨骼发育和维持中的作用存在争议。我们目前的理解是，骨的重力卸载导致骨丢失（骨质减少），其通常进展为骨质疏松症并最终骨折。这是卧床不起的病人和老年人经历的一个重要问题。在轨道上的宇航员会经历每月约1%至3%的骨质流失，这相当于地球上骨质疏松症患者一年的骨质流失。了解骨骼对不同水平重力的反应对于开发合理的药物设计或物理治疗方法以减轻骨质减少至关重要。目前，将骨骼暴露在长期缺乏重力的情况下的唯一方法是通过国际空间站上的轨道自由落体。这些研究费用昂贵，在国际空间站上进行后勤困难。研究重力对骨动力学的调节作用，理想的方法是有一种基于地面的方法来消除或减小作用在骨上的重力。创造一个放大骨丢失速率的环境将为我们提供一种工具，以加速我们对潜在基因组学、蛋白质组学和代谢组学机制的理解。拟议的研究旨在确定地面磁悬浮是否是细胞培养研究的轨道自由落体的合适模拟。研究细胞培养物而不是整个动物允许高度受控和可重复的实验。我们计划在与我们的地面悬浮磁铁和国际空间站太空微重力环境兼容的生物反应器中培养MC 3 T3成骨细胞和原代骨细胞。我们独特的悬浮磁铁集成了一个37 ℃的恒温箱，它集成在磁铁孔中，允许悬浮数周。国际空间站上实验的实施伙伴是位于科罗拉多州博尔德的生物服务空间技术公司。生物服务公司与美国宇航局合作，在向低地球轨道和从低地球轨道提供生物实验方面取得了20年的成就。在以前的轨道飞行任务中飞行的成骨细胞和破骨细胞显示出微重力影响细胞分化和基因表达的证据。所提出的研究指标包括细胞形态学研究，微阵列分析来测量差异基因表达，ELISA和RT-PCR来识别成骨细胞和破骨细胞分化的标志物，代谢组学，通过H-1 NMR光谱和MAPK，Twsg 1和NF-kB信号通路的定量。通过这套分析，我们将确定模拟微重力和国际空间站微重力环境中许多代谢物和生物标志物的相似性和差异。该项目将有助于确定可以解决的机制和途径，以减轻地球上的骨质流失。公共卫生相关性：了解骨骼对不同水平重力的反应对于开发药物设计或物理治疗的合理方法以减轻骨丢失和使人衰弱的骨折至关重要。拟议的研究旨在确定地面磁悬浮是否是细胞培养研究的轨道自由落体的合适模拟。