1. Development of Brain Organoid Platform Technologies of Drug Discovery and Disease Research

Human brain development and function rely on complex interactions among diverse cell types, including neurons, astrocytes, oligodendrocytes, microglia, and vascular cells. We are developing platform technologies to generate human iPSC-derived brain organoids that more closely recapitulate the cellular complexity and functional neural circuits of the human brain. Using brain organoids, we also investigate the processes of human brain development and maturation at the cellular and molecular levels to better understand the mechanisms underlying human brain development. Furthermore, by integrating imaging, gene expression analysis, and electrophysiological approaches, we aim to establish robust and reproducible evaluation platforms that can be applied to developmental studies, disease mechanism research, and drug discovery.

2. Development of Alzheimer’s Disease Model Brain Organoids Recapitulating Amyloid-β and Tau Pathologies

In Alzheimer’s disease, the accumulation of amyloid-β is thought to be followed by the progression of tau pathology, ultimately leading to synaptic and neural circuit dysfunction and neuronal cell death. However, the detailed mechanisms by which amyloid-β accumulation triggers tau pathology remain poorly understood. Using brain organoids generated from patient-derived iPSCs, we aim to recapitulate and investigate the progression from amyloid-β accumulation to tau pathology, together with the associated changes in neural function. By elucidating the mechanisms of disease progression at the cellular, molecular, and neural circuit levels, our goal is to identify novel therapeutic targets and contribute to the development of new treatments for Alzheimer’s disease.

3. Development of Next-Generation Computing Technologies Using Brain Organoids

The brain is a highly efficient information-processing system capable of performing complex computations with remarkably low energy consumption. We are investigating neural circuits formed within brain organoids by measuring and modulating their activity, with the goal of understanding their learning and information-processing capabilities. Using approaches such as multielectrode array (MEA) recordings and calcium imaging, we analyze neural activity and integrate these findings with AI and information science. Through this interdisciplinary approach, we aim to develop next-generation computing technologies based on the unique properties of biological neural circuits.

References

1. Shimada H, Okano H. Challenges in Dementia Research by using brain organoid technology – A next generation forebrain organoid model of dementia. Jikken-igaku (2024) [in Japanese]
2. Chen et al. Reserpine maintains photoreceptor survival in retinal ciliopathy by resolving proteostasis imbalance and ciliogenesis defects. eLife (2023)
3. Ideno et al. Human PSCs determine the competency of cerebral organoid differentiation via FGF signaling and epigenetic mechanisms. iScience (2022)
4. Shimada et al. A next-generation iPSC-derived forebrain organoid model of tauopathy with tau fibrils by AAV-mediated gene transfer. Cell Reports Methods (2022)
5. Kruczeket al. In vitro modeling and rescue of ciliopathy associated with mutations in IQCB1 (Nephrocystin 5) using patient-derived cells. Stem Cell Reports (2022)
6. Shimada et al. In vitro modeling using ciliopathy-patient-derived cells reveals distinct cilia dysfunctions caused by CEP290 mutations. Cell Reports (2017)