Research
Proposal
The aim of this research is to develop state-of-the-art molecular technologies that can facilitate the deep understanding of intracellular signal transmission and intercellular network formation in the neural systems and brain at the individual protein molecule level of resolution. Using such methods that enable to chemically label and image several key proteins such as neurotransmitter receptors, GPCRs and channel proteins in neural cells and brain tissues, the dynamic structural changes and critical functions of proteins in living cellular systems can be unveiled. Furthermore, by combining selective functional control of a target receptor in live cells with imaging techniques, we expect to analyze and clarify the complicated intercellular networks involving target receptor proteins for memory formation in brain. For this objective, this proposal will attempt to develop a new live-cell organic chemistry that can modify and regulate the target protein under the living cell conditions, which should be unique and complimentary to conventional chemical genetics or optogenetics approaches. In addition to developing these molecular technologies in the basic research fields of neuroscience and chemical biology, I am aiming to create a new field, a really interdisciplinary research area, termed neuro-chemical biology, which should be critically important between chemistry, biology and neuroscience toward a goal including development of innovative technologies for diagnosis and treatment of brain and neurological disorders such as schizophrenia and dementia.
Research Groups
In this project, we will develop biocompatible organic chemistries for protein modification and technologies that enable control of protein function, which are applied to complicated cultured neurons and brain tissues. Furthermore, we will try to elucidate the molecular mechanisms of neurophysiological phenomena in behavior and memory of animal individuals by the molecular technologies developed in this project.We will set up four research groups and address this challenge by the creation of a novel interdisciplinary research field, that is, “neurochemical biology”.
Research Group 1 (Group Leader: Tamura):
Development of new live-cell organic chemistry
This group will exploit new biocompatible organic chemistry to create molecular probes that realize chemical labeling and imaging analysis of proteins present in neuronal cells, brain tissue and living animals. Specifically, based on our previous achievements, we aim to develop the following two fundamental technologies and sophisticate them to a level applicable to the nervous system. The molecular probes created in this group will be further improved by reflecting the feedback from brain slice and in vivo test conducted in Research Groups 3 and 4, and finally become powerful neurochemical tools that take into consideration the pharmacokinetics and metabolic stability.
Research outline of group1
Research Group 2 (Group Leader: Nonaka):
Development of methods for controlling protein activity
This group will develop novel chemogenetic and optochemogenetic methodologies to artificially regulate the activity of a target receptor with precise timing using chemicals or light, and attempt to elucidate the correlation between the function of the receptor molecule and the neural networks.
Research outline of group 2
Research Group 3 (Group Leader: Kiyonaka):
Strategies for imaging and regulation of neuron and brain tissue
In this group, we examine the applicability of the new methods for visualizing or controlling neuronal proteins, which are developed by Tamura and Hamachi group, in cultured neurons or brain tissues. In brain tissue, not only neurons but also several kinds of glial cells are expressed to maintain neuronal functions. Neurons are further divided into sub-groups, each of which has own roles in neuronal circuits. Here, we develop novel methods for chemogenetic regulation of receptors in a cell-specific manner, and evaluate drug transport in vivo. This group also develops a new chemical labeing method for visualizing newly identified proteins by Tamura group in animals.
Research outline of group 3
Research Group 4 (Group Leader: Kakegawa):
Clarifying physiological roles in animals using molecular technologiesl
Research purpose of this group is identifying direct correlation between brain function and proteins in animals. In the human brain, about 100 billion nerve cells are communicated each other via synapses, which enables constructing neural circuits to process a huge number of information. Recently, optogenetics and chemogenetics, which enable artificially controlling individual nerve cells by external stimuli, have been utilized for understanding neural circuits. However, these methods are just utilized for controlling the activity of nerve cells, and cannot be applied for elucidating the dynamics of synapses. Neural circuits are not static but more dynamically changed by neuronal activity, which is called "synaptic plasticity". Synaptic plasticity is considered as the cellular basis of memory and learning, and its abnormality causes various mental and neurological disorders. Therefore, it is essential to elucidate the molecular mechanisms of synaptic plasticity in order to understand the detailed mechanism of our memory and mental/neurological diseases. In this group, we apply our chemogenetic methods in brain slices to confirm utility of our method, and then apply these methods in live animal to elucidate correlation between receptor dynamics and brain functions.
Research outline of group 4