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

通过该奖项，化学部生命过程化学项目资助康奈尔大学化学和化学生物学系的Jeremy Baskin博士开发化学探测器，以研究由脂质磷脂酸介导的对社会成员的健康和福祉至关重要的生物信号通路。脂类是一种防水分子，在生物系统中，它可以作为能量储存、细胞膜的主要成分和细胞内的信号分子。在后一种能力中，信号脂质如磷脂酸作为第二信使，导致细胞改变其新陈代谢、基因表达和行为，以响应不同的细胞外刺激。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，能够可视化和干扰这种关键信号脂质的产生是至关重要的。这项拟议的研究描述了报告和控制磷脂酸合成的化学和生化工具，以及它们在研究被认为受磷脂控制的重要信号通路方面的应用。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，该计划针对初中和高中服务不足的人群，开展关于脂质和生物膜的动手推广活动，以提高年轻女性和未被充分代表的少数族裔学生的科学意识和兴趣。根据上下文的不同，脂质第二信使磷脂酸可以刺激蛋白激酶导致细胞生长和增殖，肌动蛋白聚合促进细胞迁移，以及囊泡萌芽增加蛋白质分泌。一种脂质信号如何引起如此多样的生理事件仍然是一个谜。剖析磷脂酸的各种功能后果的主要障碍是缺乏工具来可视化和调节其产生的时空控制。这项建议的研究目标是开发一种化学方法来成像活细胞内产生磷脂酸的细胞内位置，开发一种化学酶策略，使之能够在活细胞内精确的亚细胞位置根据需要产生磷脂酸，并应用这些工具来探索关于溶酶体中磷脂酸在协调细胞生长途径中所起作用的机制问题。这项工作将产生研究脂信号的新方法和关于单一脂信号制剂如何指导精确的细胞信号结果的基础知识。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.