Supply and Demand of Proteins During Neuronal Growth and Extension

神经元生长和延伸过程中蛋白质的供需

• 批准号: 0932590
• 负责人: Sameer Shah
• 金额: $ 29.78万
• 依托单位: University of Maryland, College Park
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2012-05-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0932590&HistoricalAwards=false
• 关键词: Supply; Demand; Proteins; During; Neuronal

0932590ShahINTELLECTUAL MERITThis project addresses the fundamental relationship between the production, delivery, and demand of neuronal proteins during axonal growth. The global hypothesis to be tested is that axonal transport and local protein production are primary suppliers for the resources needed for neuronal growth, and are regulated in part by the local mechanical environment of the neuron. This hypothesis will be addressed by using a multidisciplinary approach involving molecular and cellular biology, high-resolution imaging and image processing, and cell biomechanics.Any number of candidate proteins may be selected to study neuronal supply and demand. However, the specific cargoes to be considered in this project are those essential for growth, transport, and protein synthesis: mitochondria, responsible for fulfilling ATP-dependent energetic requirements for the neuron, vacuoles, responsible for supplying plasma membrane required for expansion of neuronal surface area; ribosomes, responsible for protein synthesis; and mRNA, which provides the template transcript for protein synthesis.Several aspects of the proposed research are transformative, including the development of novel engineering approaches to examine and quantify neurobiological processes, and the use of a systems approach to understand the subcellular function of neurons. In the long term, this basic science project has implications for providing a basis for the progression of neurodegenerative diseases linked to defects in axonal transport, such as Alzheimer's and Lou Gehrig's Disease (ALS). Additionally, this bioengineering approach to understanding physiological processes within the neuron will facilitate a valuable data-driven approach to modeling and manipulating the dynamics of neuronal cargo supply and demand, and the allocation of cellular resources. Finally, given the ubiquity of transport processes in cellular systems, it is expected that general principles identified from this project will be relevant to the function and dysfunction of non-neuronal cells. BROADER IMPACTS In addition to the biomedical and basic scientific impacts highlighted above, the proposed plan also impacts education, research training, and community outreach. In the classroom, research results will be integrated into two bioengineering courses based on cell physiology, both of which draw heavily on current research approaches for their course material. Given the multi-disciplinary nature of the proposed research, training opportunities for undergraduate and graduate students from backgrounds in both engineering and biological sciences will be provided. Thus far, students from multiple backgrounds have successfully been recruited to the laboratory of the PI, and the continuation of this success is anticipated based on the emphasis on an open, collaborative work environment. This cross-disciplinary, team-based approach is critical for training a new generation of biomedical scientists and bioengineers. Additionally, participation in a variety of outreach programs will be initiated or continued. A new Neuro-Bioengineering Research Program (NBRP) will be created, in conjunction with the QUEST program at Eleanor Roosevelt High School, whose enrollment consists of student populations under-represented in science and engineering. Implementation has already been started for portions of this program, which exposes middle and high school students to career options in bioengineering, introduces them to research methodology and scientific writing, and provides them with access to state-of-the-art laboratory facilities. Active participation in the Molecular and Cellular Bioengineering Research Experiences for Undergraduates (REU) Program will also be continued. It is a priority to admit students to this program who have limited access to research opportunities at their home institutions. The vision of the PI is consistent with that of the Fischell Department of Bioengineering, the Clark School of Engineering, and the University of Maryland; ultimately, the aim is to encourage and facilitate the participation of K-12, undergraduate, and graduate students in multidisciplinary biomedical research, in an effort to attract the finest students to this exciting field.

0932590 Shahintellectual merit该项目解决了轴突生长过程中神经元蛋白质的生产，交付和需求之间的基本关系。有待检验的全局假设是，轴突运输和局部蛋白质产生是神经元生长所需资源的主要供应者，并且部分受神经元的局部机械环境调节。这一假设将通过使用涉及分子和细胞生物学、高分辨率成像和图像处理以及细胞生物力学的多学科方法来解决。可以选择任何数量的候选蛋白来研究神经元的供应和需求。然而，在这个项目中要考虑的特定货物是那些对生长、运输和蛋白质合成至关重要的货物：线粒体，负责满足神经元的ATP依赖性能量需求;空泡，负责供应神经元表面积扩张所需的质膜;核糖体，负责蛋白质合成;和mRNA，它为蛋白质合成提供模板转录本。拟议研究的几个方面是变革性的，包括开发新的工程方法来检查和量化神经生物学过程，以及使用系统方法来理解神经元的亚细胞功能。从长远来看，这一基础科学项目具有为与轴突运输缺陷相关的神经退行性疾病的进展提供基础的意义，如阿尔茨海默氏症和Lou Gehrig病（ALS）。此外，这种理解神经元内生理过程的生物工程方法将促进有价值的数据驱动方法来建模和操纵神经元货物供应和需求的动态以及细胞资源的分配。最后，考虑到细胞系统中运输过程的普遍性，预计从该项目中确定的一般原则将与非神经元细胞的功能和功能障碍相关。除了上面强调的生物医学和基础科学影响外，拟议的计划还影响教育，研究培训和社区推广。在课堂上，研究成果将被整合到基于细胞生理学的两门生物工程课程中，这两门课程都在很大程度上借鉴了当前的研究方法。鉴于拟议研究的多学科性质，将为工程和生物科学背景的本科生和研究生提供培训机会。到目前为止，来自不同背景的学生已经成功地被招募到PI的实验室，并预计这种成功的延续是基于对开放，协作工作环境的重视。这种跨学科，以团队为基础的方法是培养新一代生物医学科学家和生物工程师的关键。此外，将开始或继续参与各种外联方案。一个新的神经生物工程研究项目（NBRP）将与埃莉诺·罗斯福高中的QUEST项目一起创建，该项目的入学人数由科学和工程专业人数不足的学生组成。该计划的部分内容已经开始实施，该计划使初中和高中学生接触生物工程的职业选择，向他们介绍研究方法和科学写作，并为他们提供最先进的实验室设施。积极参与分子和细胞生物工程研究经验的本科生（REU）计划也将继续。这是一个优先录取学生谁有机会在自己的家乡机构有限的研究这个程序。PI的愿景是与生物工程，克拉克工程学院和马里兰州大学的财政部一致的;最终，目的是鼓励和促进K-12，本科生和研究生参与多学科生物医学研究，努力吸引最优秀的学生到这个令人兴奋的领域。