We are working on the mechanism underlying homeostatic regulation of the central nervous system in health and diseases.
1. Development and function of neurovascular unit
he weight of human brain is only 2% of the body weight. However, 15% of the blood from the heart is circulating through the brain, providing the oxygen, nutrients and various signaling molecules. Blood-brain-barrier, a special barrier in brain vessels, protects brains from harmful substances in blood. Blood-brain-barrier is known to restrict the translocation of the drug from blood to brains. Drugs aiming to cure the central nervous system are therefore critically influenced by the blood-brain-barrier. Aging and the environmental factors are known to affect the properties of blood-brain-barrier.
Recent studies showed that the blood-brain-barrier is formed by a complex interactions among vascular endothelial cells, vascular pericytes and astrocytes and neurons. These cells are orderly placed in brain capillaries, and the structure is called as neurovascular unit. Neurovascular unit may not only protect brains but also control local blood flow levels in brains and support the stem cell that play important roles in the recovery from ischemic brain damages.
We are investigating the molecular mechanisms controlling development and functions of neurovascular units in mammalian brains in terms of the transcription factors and intra and intercellular signaling molecules. The project is promoted by usage of originally developed mutant mice and the in vitro blood-brain-barrier model that is developed by former professor, Dr. Masami Niwa, and his colleagues.
2. Molecular functions and physiological roles of synaptic transmembrane proteins.
Neurons in brains form numerous synapses to transmit signals among them. Synaptic transmission is mediated by neurotransmitter, stored in synaptic vesicles in presynapse, and released extracellularly upon the excitation. Postsynaptic receptors transduce the signals caused by the neurotransmitter binding. The presynapse and postsynapses are aligned with a narrow space called as synaptic cleft where many plasma membrane-associated proteins (so called synaptic “adhesion” molecule) exist (below figure).
The functional morphological properties of the synapses in mammalian brains are highly divergent. Recent studies have been revealing that the diversity partly reflects the variety of the synaptic membrane-associated proteins. While many synaptic membrane-associated proteins are known, we chose the candidate molecules firstly based on their structural and expression profiles and then address their physiological role through the analysis of the genetically manipulated mice.
3. Clarification of the pathophysiology underlying neurodevelopmental disorders
Advances on genomics and genetic analysis have been revealing many genetic factors involved in the pathogenesis. On the other hand, our bioinformatics-based candidate gene approach has been bearing fruits such as neurological disorder model animals. These include the holoprosencephaly (Zic2 knockdown), Dandy-Walker malformation (cerebellar dysgenesis, Zic1 null), Schizophrenia (Lrrtm1 null), deafness/myopia comorbidity (Slitrk6 null). In addition, others are partly mimicking the pathophysiology of the patients of Tourette’s syndrome, autism, epilepsy and attention-deficit hyperactive disorders. The disease model animals are being multi-disciplinarily analyzed to clarify the core disease mechanisms and to improve the pharmacotherapy.