Interdisciplinary project aims to decode human kinome in brain function and disease

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The Chan Zuckerberg Initiative (CZI) announced four multi-year Exploratory Cell Networks grants for researchers exploring the frontiers of genomics, cell biology, and synthetic biology by developing new measurement technologies. The projects will be bringing together regional labs in California, the Mid-Atlantic, and the Research Triangle.

Klaus Hahn, PhD, the Ronald G. Thurman Distinguished Professor of Pharmacology and member of the UNC Lineberger Comprehensive Cancer Center, will be co-leading a project titled, "Research Triangle: Revealing the Hidden Topologies of the Human Kinome" with Scott Soderling, PhD, a cell biologist at Duke University and Albert Keung, PhD, a chemical and biomolecular engineer at North Carolina State University.

Each of the three institutions will receive a million dollars, awarded over three years, with potential extension into future years. The three investigators share leadership of this effort, which is made possible by interlocking the diverse technologies of their labs.

The Triangle groups will focus on the "kinome", a set of over 500 proteins that function as "molecular switches" crucial to nervous system function, neurological disease, and a range of non-neurological disorders. p38 kinases, for example, respond to stress stimuli and are involved in cognitive and emotional functions, including anxiety, neurodegeneration, and high-level decision making.

Much work has led to an understanding of specific kinases and how they function. Because kinases work together as members of large circuits, it is also important for researchers to see how they affect one another and operate as a whole.

This is the goal of the new project -; which combines the Keung lab's ability to map out the connections and interactions among many kinases, the Soderling lab's ability to understand how these connections are placed and act within the brain, and the Hahn lab's ability to see and control kinase activities in real time to understand how transient activation events regulate the circuitry.

The researchers are developing new tools to correlate information about these different aspects of kinase behavior, and to study kinases at scale inside the neural system of a living organism (in vivo). The Keung lab is creating new instruments and molecular screening approaches to provide precise, quantitative information about which kinases interact and how fast and tight these interactions are.

The Soderling group will probe kinase activities in living brains, examining which of these potential interactions occur during specific behaviors. The Hahn lab will develop capabilities to stop or start kinases in live brains, and to visualize their activation in real time. This information will be brought together by Soderling at Duke using an integrated computational model of the human kinome.

This multi-faceted research project, which includes tool development, experimental application and modeling, has implications for tackling many other types of proteins and other high-dimensional cell biological problems, spanning multiple human diseases. The ultimate goal of this project is to identify new therapeutic targets in the brain, and to generate novel diagnostic tools that report and interpret dynamic changes in the human kinome.

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