CAREER: Chemical Tools to Study Phosphatidic Acid Signaling Integrated with Educational Outreach in the Chemical Biology of Lipids

有了这个奖项，化学部的生命过程化学计划正在资助康奈尔大学化学与化学生物学系的杰里米巴斯金博士开发化学探针，以研究对社会成员的健康和福祉至关重要的生物信号通路，这些通路由脂质磷脂酸介导。脂质是防水分子，在生物系统中，可以作为能量储存、细胞膜的主要成分和细胞内信号分子。在后一种能力中，信号脂质如磷脂酸作为第二信使起作用，导致细胞改变其代谢、基因表达和响应于多种细胞外刺激的行为。为了阐明细胞内产生磷脂酸的位置如何与每种不同的生理结果相关，关键是能够可视化和干扰这种关键信号脂质的产生。拟议的研究描述了报告和控制磷脂酸合成的化学和生物化学工具，以及它们在研究被认为受这种脂质控制的重要信号通路中的应用。这项研究旨在更深入地了解脂质的化学和生物化学，并与一项教育计划相结合，该计划需要针对初中和高中服务不足的人群开展脂质和生物膜的实践推广活动，以提高年轻女性和代表性不足的少数民族学生对科学的认识和兴趣。刺激蛋白激酶以引起细胞生长和增殖、肌动蛋白聚合以促进细胞迁移和囊泡出芽以增加蛋白分泌。一个脂质信号如何引起如此多样的生理事件仍然是一个谜。解剖磷脂酸的各种功能后果的主要障碍是缺乏可视化和调节其生产与时空控制的工具。该提案的研究目标是开发一种化学方法来成像活细胞内磷脂酸生产的细胞内位点，开发一种化学酶促策略，使磷脂酸的生产在活细胞内的精确的亚细胞位置的需求，并应用这些工具来探测磷脂酸在溶酶体中的作用的机械问题，在编排细胞生长途径。这项工作将产生两个新的方法来研究脂质信号和基础知识，如何一个单一的脂质信号剂可以直接精确的细胞信号outcome.This奖项反映了NSF的法定使命，并已被认为是值得的支持，通过评估使用基金会的智力价值和更广泛的影响审查标准。

With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Jeremy Baskin from the Department of Chemistry and Chemical Biology at Cornell University to develop chemical probes to study biological signaling pathways vital to the health and well-being of members of society, that are mediated by the lipid phosphatidic acid. Lipids are water-repellant molecules that, in biological systems, can act as energy stores, major constituents of cellular membranes, and intracellular signaling molecules. In the latter capacity, signaling lipids such as phosphatidic acid function as second messengers that cause cells to change their metabolism, gene expression, and behavior in response to diverse extracellular stimuli. To elucidate how the locations within the cell where phosphatidic acid is produced relates to each different physiological outcome, it is critical to be able to visualize and perturb the production of this key signaling lipid. The proposed research describes chemical and biochemical tools to both report on and control phosphatidic acid synthesis, as well as their application to study an important signaling pathway thought to be under the control of this lipid. This research to gain a deeper understanding of the chemistry and biochemistry of lipids integrates with an educational plan that entails hands-on outreach activities on lipids and biomembranes targeted at underserved populations in middle and high school, to increase awareness of and interest in science in young women and underrepresented minority students.The lipid second messenger phosphatidic acid can, depending on the context, stimulate protein kinases to cause cell growth and proliferation, polymerization of actin to promote cell migration, and vesicle budding to increase protein secretion. It remains a mystery how one lipid signal can cause such diverse physiological events. The main impediment to dissecting the varied functional consequences of phosphatidic acid is a lack of tools to visualize and modulate its production with spatiotemporal control. The research objectives of this proposal are to develop a chemical method to image intracellular sites of phosphatidic acid production within live cells, to develop a chemoenzymatic strategy to enable production of phosphatidic acid on demand at precise, subcellular locations within live cells, and to apply these tools to probe mechanistic questions about the role of phosphatidic acid at lysosomes in orchestrating cell growth pathways. This work will generate both new methodologies for studying lipid signaling and fundamental knowledge into how a single lipid signaling agent can direct precise cellular signaling outcomes.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.