Chemical Probes and Assessing Rab7 and Accessory Protein Function

化学探针和评估 Rab7 及辅助蛋白功能

• 批准号: 0956027
• 负责人: Angela Wandinger-Ness
• 金额: $ 103.23万
• 依托单位: University of New Mexico Health Sciences Center
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-15 至 2016-02-29
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0956027&HistoricalAwards=false
• 关键词: Chemical; Probes; Assessing; Rab7; Accessory

The intellectual merits of the research are in discovering how a fundamental cell process works, coupled with the development of new chemical agents and cutting edge technologies. Cells depend on cues that they receive from the external environment to grow, divide and survive. Plant and animal (including human) cells have evolved complex pathways for recognizing and internalizing cargo molecules from the external milieu and shuttling the cargo to various subcellular locations for processing. The pathways that govern the handling of internalized cargo are present in all cells except bacteria and are governed by evolutionarily conserved escort proteins. These regulatory escort proteins function together as a molecular machine that must be dynamically assembled and dissassembled according to the cargo and its subcellular destination. The objective of the research is to unravel how a subset of regulatory escort proteins in animal cells (Rab7 GTPase, MTMR13 lipid phosphatase, hVps39 nucleotide exchange factor and TBC1D15 GTPase activating protein) recognize one another and are assembled into a functional machine that appropriately delivers its cargo. Failure of the machine components to work together leads to a failure of the cell to survive. The research also develops novel chemical probes, which is applicable to the study of a family of small GTPases with 100 members. The project combines state-of-the-art visualization of cellular processes; chemical biology and novel compound identification for pathway dissection; and quantitative biology for accurate measurement all with the goal of acquiring mechanistic understanding of escort proteins that are central to cell function and viability. The broad impact of the project is increased scientific literacy and elucidation of processes that are fundamental to all cells; the manipulation of which may have technologic advantage. The head of the program is an experienced mentor, expert in cell biology, biochemistry and advanced microscopic imaging and active in science education outreach to public and secondary school students. She serves as a board member of New Mexico Academy of Science, mentor on several grant funded training programs, director of science teaching certificate program and a post-doctoral fellow training program. These activities: 1) provide students and underrepresented minorities with hands-on experience with cutting edge science that prepare them to assume productive science and technology intensive careers, 2) increase public awareness and understanding of current topics and debates in science ranging from stem cells to evolution and 3) engage the next generation of young people to work as part of an interdisciplinary team and invent new ways to tackle central problems in biology. The pathway and Rab7 GTPase being studied is also relevant in plants where it is related to plant growth, pollen production, fruit ripening and nitrogen fixation. Thus, knowledge of these processes is also the underpinning of agricultural technology development that seeks to manipulate the pathways for increased crop production and environmental sustainability through biological nitrogen fixation.

这项研究的智力价值在于发现基本的细胞过程是如何工作的，再加上新化学试剂和尖端技术的发展。 细胞依赖于它们从外部环境接收到的信号来生长、分裂和生存。 植物和动物（包括人类）细胞已经进化出复杂的途径，用于识别和内化来自外部环境的货物分子，并将货物穿梭到各种亚细胞位置进行处理。 控制内化货物处理的途径存在于除细菌之外的所有细胞中，并且由进化上保守的护送蛋白控制。 这些监管护送蛋白作为一个分子机器，必须根据货物和其亚细胞目的地动态组装和拆卸一起发挥作用。 该研究的目的是揭示动物细胞中的一组调节护送蛋白（Rab 7 GTPase、MTMR 13脂质磷酸酶、hVps 39核苷酸交换因子和TBC 1D 15 GTPase激活蛋白）如何相互识别并组装成适当递送其货物的功能机器。 机器部件不能一起工作导致细胞不能存活。 该研究还开发了新的化学探针，适用于研究一个拥有100个成员的小GTP酶家族。 该项目结合了最先进的细胞过程可视化;化学生物学和用于通路解剖的新型化合物鉴定;以及用于精确测量的定量生物学，所有这些都是为了获得对细胞功能和活力至关重要的护送蛋白质的机械理解。该项目的广泛影响是提高科学素养和阐明对所有细胞都至关重要的过程;对这些过程的操纵可能具有技术优势。 该计划的负责人是一位经验丰富的导师，细胞生物学，生物化学和先进的显微成像专家，并积极参与公共和中学学生的科学教育宣传。 她是新墨西哥州科学院的董事会成员，几个资助培训项目的导师，科学教学证书项目主任和博士后研究员培训项目。 这些活动：1）为学生和代表性不足的少数民族提供尖端科学的实践经验，使他们为从事生产性科学和技术密集型职业做好准备，2）提高公众对当前科学主题和辩论的认识和理解，从干细胞到进化，3）让下一代的年轻人作为跨学科团队的一部分参与工作，并发明新的方法来解决生物学中的核心问题。 所研究的途径和Rab 7 GT3在植物中也是相关的，其中其与植物生长、花粉产生、果实成熟和固氮相关。 因此，对这些过程的了解也是农业技术发展的基础，农业技术发展试图通过生物固氮来控制增加作物产量和环境可持续性的途径。