CAREER:Discovery and characterization of inositol polyphosphates as mediators of protein pyrophosphorylation

几乎细胞生物学的每个方面都依赖于小分子信使，这些信使的功能是沟通和整合有关细胞环境，生长条件和可用营养素的信息;并且还在相邻细胞之间传递信息。 该项目旨在发现和定义肌醇焦磷酸的第二信使作用，肌醇焦磷酸是一种新颖且普遍存在但特征不明显的一类高能分子。 到目前为止，每一个被检测的真核生物都被发现含有肌醇焦磷酸，从单细胞生物到植物，再到人类。为什么细胞要花费能量合成这些分子，或者它们在生物学中的确切机制作用在很大程度上还没有被探索。 在此之前，肌醇焦磷酸已经涉及从维持DNA完整性到调节可用细胞能量库的各种细胞过程。 使用新开发的方法，克服了阻碍这个年轻和欠发达的研究领域的挑战，该项目旨在确定广泛的生物学作用和肌醇焦磷酸独特的信号传导能力。 更具体地说，这些高能分子已被证明能够通过将高能磷酸转移到蛋白质底物来修饰细胞蛋白质，这是一种产生称为蛋白质焦磷酸化的新修饰的事件。 通过新的实验方法，已经发现数百种跨越真核生物的蛋白质被焦磷酸化。 本计画将开始定义蛋白质焦磷酸化作用的过程，重点是探讨焦磷酸肌醇如何影响这些蛋白质的功能。 该项目的最终目的是（1）描述一个新的和可扩展的信号系统，（2）构建一个开放的实验框架，用于在不同的生物学背景下进行调查。更广泛的影响与该项目相关的教育活动有目的地并列并加强基础，基础研究活动以及跨越各级教育的背景下建立的转化研究课程。他们特别注重学生在传统的医生，科学家预备课程的培训，以提供基础，基础研究的机会和经验，以及支持基础研究的关键和必要的作用的真实理解。 教育计划将为学生提供研究机会，作为多元化环境的一部分，并特别关注高中，本科和医学院学生的外联和基础研究培训，并针对代表性不足的少数民族和妇女的包容性进行方案努力。

Intellectual MeritNearly every aspect of cell biology depends on small molecule messengers that function to communicate and integrate information about the cellular environment, growth conditions, and available nutrients; and also relay information between neighboring cells. This project aims to discover and define the second messenger roles of inositol pyrophosphates, a novel and ubiquitous, yet poorly characterized class of high-energy molecules. To date, every eukaryotic organism examined has been found to contain inositol pyrophosphates, from unicellular organisms, to plants, to man. Why cells expend energy synthesizing these molecules or what precise mechanistic roles they have in biology has remained largely unexplored. Previously, inositol pyrophosphates have been implicated in diverse cellular processes ranging from the maintenance of DNA integrity to regulating available cellular energy pools. Using newly developed methodologies that overcome challenges that have stymied this young and underdeveloped research field, this project seeks to define the wide-reaching biological roles and unique signaling capacity of the inositol pyrophosphates. More specifically, these high energy molecules have been shown to be capable of modifying cellular proteins by transferring an energetic phosphate to protein substrates, an event that generates a novel modification termed protein pyrophosphorylation. Through new experimental modalities hundreds of proteins that span the breadth of eukaryotic organisms have been found to be pyrophosphorylated. This project will begin the process of defining the roles of protein pyrophosphorylation by focusing on, and examining how inositol pyrophosphates affect the function of these proteins. The project's ultimate endpoints are (1) the description of a new and expansive signaling system and (2) the construction of an open experimental framework for its investigation in diverse biological contexts.Broader ImpactsThe educational activities associated with the project purposefully juxtapose and reinforce basic, fundamental research activities alongside established translational research curricula in a context that spans all levels of education. They specifically focus on the training of students in traditional physician-scientist preparatory programs in order to provide fundamental, basic research opportunities and experiences, as well as support an authentic understanding of the critical and necessary roles of basic research. The educational programs will provide research opportunities to students as part of a diverse environment and focus in particular on outreach and basic research training of high school, undergraduate, and medical school students with programmatic efforts directed at the inclusion of under-represented minorities and women.