Chemical Probes and Assessing Rab7 and Accessory Protein Function

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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.