NSF Award
1253809
Intellectual Merit<br/>Nearly 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.<br/><br/>Broader Impacts<br/>The 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.
