Kei Igarashi

Age-induced impairment of entorhinal cortex-projecting dopamine neurons

Grant No.：JPMJPR2481

Researcher : Kei Igarashi

Outline

This study aims at elucidating the anatomical, physiological, and molecular mechanisms of age-related dysfunction in entorhinal cortex-projecting dopamine neurons, critical for memory encoding. As the entorhinal cortex is the brain region exhibiting the earliest pathophysiological alterations in Alzheimer’s disease, this study is expected to lay a foundation in understanding Alzheimer’s disease pathophysiology.

Sayaka Inoue

Neuroendocrinological understanding of behavioral changes during menopause

Grant No.：JPMJPR2482

Researcher : Sayaka Inoue

Outline

Menopause is an age-related transformation that occurs in women in their 40-50s. Along with reproductive aging, ovarian sex hormone levels gradually decrease and this can alter the central nervous system functions. This study aims to identify the mechanistic basis underlying behavioral changes during reproductive aging. Using the neural circuits that control social behavior as a model system, we address the neuroendocrinological mechanisms that link reproductive aging and behavioral changes by use of molecular, anatomical, physiological, and behavioral analyses.

Hiroyuki Uechi

Exploring metabolites regulating intracellular protein thermodynamics

Grant No.：JPMJPR2483

Researcher : Hiroyuki Uechi

Outline

Deteriorating intracellular protein dynamics is a hallmark of ageing and the associating diseases, such as protein aggreation and mislocalization. Little is known about how cells generate intracellular environments which give proteins physiological dynamics. Recent emerging insights suggest that intracellular dynamics of biomolecules emerge based on their thermodynamics, such as phase separation, which can be modulated by small molecules. This study aims to unveil a cellular mechanism by which living systems tune protein dynamics using endogenous small molecules, that is, intracellular metabolites, which may underlie physiological protein dynamics and its disfucntion in ageing.

Manami Oya

Mechanism of interaction between age-dependent alternation of primary cilia and aging

Grant No.：JPMJPR2484

Researcher : Manami Oya

Outline

Melanocortin type 4 receptor (MC4R), which increases energy expenditure in response to satiety signals, localizes in primary cilia of hypothalamic neurons. Primary cilia are fibrous structures that protrude from a cell body and act as antennae by bearing receptors. MC4R-bearing primary cilia shorten with age, leading to an age-dependent reduction in metabolism. In this project, I aim to elucidate the mechanism of age-dependent shortening of MC4R-bearing primary cilia. First, I will search for factors involved in the age-dependent shortening by using scRNA-seq and validate them in cultured cells and animals. I believe that the knowledge gained from this project will provide clues to elucidate the mechanism of age-related decline in various physiological functions from the perspective of primary cilia.

Akifumi Shiomi

Understanding of age-related organismal transformations through cell mechanics

Grant No.：JPMJPR2485

Researcher : Akifumi Shiomi

Outline

Cell surface mechanics plays a pivotal role in numerous biological contexts including aging. However, the transcriptional regulation underlying the change in the cell surface mechanics and its causal relationships largely remain to be uncovered because of the limited tools to interrogate the link between the mechanical properties and the molecular regulation. This project aims to elucidate the complex relationship between cellular mechanics and gene regulation in aging by applying ELASTomics (electroporation-based lipid-bilayer assay for cell surface tension and transcriptomics), the analytical method that enables comprehensive measurement of gene expression and cell surface tension at the single-cell resolution.

Mio Nakanishi

Understanding of Aging Through Alterations in Hematopoietic Cell Spatial Organization Dynamics

Grant No.：JPMJPR2486

Researcher : Mio Nakanishi

Outline

In this project, we aim to establish a framework for understanding and suppressing the progression of hematopoietic aging phenomena, based on our discovery of a novel regulatory mechanism involving the spatial organization of hematopoietic stem and progenitor cells. Additionally, we seek to unravel the underlying mechanisms of aging that lead to deterioration across various tissues, such as disruptions in quiescence and skewed differentiation.

Takashi Namba

Understanding the cause of neurodegeneration from human evolution

Grant No.：JPMJPR2487

Researcher : Takashi Namba

Outline

During the evolution, human has acquired brain with significantly improved cognitive functions. It has been shown that human brain evolution is driven by mechanisms characteristic to human. This project will investigate a potential involvement of such mechanisms by utilizing patient-derived iPS cells and multi-omics to understand the novel etiology of neurodegenerative diseases.

Yoshitaka Matsuo

The connection between age-dependent alteration of translational dynamics and the hallmarks of aging.

Grant No.：JPMJPR2488

Researcher : Yoshitaka Matsuo

Outline

It has been reported in recent years that the frequency of translation stalling increases with aging, leading to the worsening of proteostasis disruption. This project focuses on age-dependent translational stalling, aiming to elucidate the molecular mechanisms behind the increased translation stalling caused by aging and the accumulation of its products. Additionally, by investigating the possibility that translation stalling associated with aging stimulates the various types of hallmarks of aging, we aim to contribute to a fundamental understanding of the biological changes that occur with aging.

Akihiro Matsumoto

Understanding of the neural basis for aging of the retinal computation

Grant No.：JPMJPR2489

Researcher : Akihiro Matsumoto

Outline

This project aims to understand the neural basis for functional alteration of the retinal computation by aging. We will reveal the impact of deteriorated retinal inputs on the central nervous system, such as vision, sleeping, and cognition, by using physiology, imaging, genetics, behavioral analysis, and mathematical modeling. Based on the findings of this project, we will aim to establish a novel therapeutic strategy for restoring the dysfunction in the central nervous system by interventional manipulation of retinal function.

Yuka Mitsuhashi(Koike)

Deciphering Neurodegeneration via DNA Damage by Age-Dependent Demethylation

Grant No.：JPMJPR248A

Researcher : Yuka Mitsuhashi(Koike)

Outline

One of the significant risk factors for sporadic neurodegenerative diseases is aging. In this study, I focused on DNA demethylation and DNA damage as inducers of neurodegeneration, which are age-dependent molecular mechanisms. I aim to decipher the molecular mechanisms of age-related neurodegeneration by combining the state-of-the-art technologies of single nuclear epi-transcriptome and DNA damage site analyses in human brains with neurodegenerative diseases.