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Team Project Name and for patients (e.g., FDG-PET, A-PET, Tau-
PET) to more sensitively detect reduced neural
Treatment of Alzheimer's disease by overcoming activity due to energy depletion. These methods
energy crisis help us to unravel the molecular mechanisms
Research Project of ENTs on the progression of AD. We will also
While a few therapeutic antibodies for Alzheimer's investigate how the functions of the glymphatic
systems can be improved with the treatment of
disease (AD) have been approved for clinical ENT inhibitors. Furthermore, we will apply cryo-
uses, they target only a limited population and electron microscopy to provide high-resolution
come at a high cost. On the path of investigating structures of ENTs, which will greatly facilitate more
the pharmacological action of the active ingredient effective discovery of novel drugs.
of a Chinese herbal medicine, Gastrodia elata,
evidences showed that its underlying mechanism Key Words
is highly correlated with the restoration of energy Equilibrative nucleoside transporters (ENTs),
homeostasis in the brain, especially through Alzheimer's disease drug development, adenosine,
the inhibition of the equilibrative nucleoside glymphatic systems, positron emission tomography,
transporters (ENTs). Adenosine, one of the major functional magnetic resonance imaging, cryo-
substrates of ENTs, serves multiple functions in the electron microscopy, drug design.
body, and the subtle regulation of its intracellular
and extracellular concentration in the brain exerts Global Cooperation
profound effects on the neuronal health.
1. Investigate the physiological and pathological
functions of ENTs in brain cells (neurons,
Our previous studies with AD mice showed that astrocytes, microglia) and conduct behavioral
inhibiting ENT1 can alleviate the brain energy analyses in gene-deficient mice.
deficit caused by tauopathy and slow down AD- 2. Research and develop potential mechanisms of
related pathological symptoms. Besides, ENT1 may ENT1 drug(J4) for treating Alzheimer's disease
serve as a therapeutic target for neuroinflammation (AD).
and enhancing functional recovery in mice with 3. Study the effects of ENTs on clearing abnormal
spinal cord injuries. On the other hand, deletion protein accumulation through the glymphatic
of ENT2 can interfere with energy metabolism flow.
and deteriorates motor function in a mouse model 4. Investigate the structure of ENTs by cryo-EM and
of Huntington's chorea. On the contrary, the focus on the development of ENTs antagonists
removal of ENT2 can protect the neurons against and agonists.
inflammation in the mouse brain and facilitate the 5. Establish PET and MRI methods for brain
integrity of the blood-brain barrier. The results imaging in humans and small animals and apply
of these studies indicate the complex roles and them in research for ENTs drug development.
multifaceted functions of ENTs in various contexts.
Project Web Page
In this project, we focus on elucidating the roles
and functions of ENT1 and ENT4 in brain neurons,
ENT2 in astrocytes, and ENT3 in microglial cells,
with the aim to provide the effective strategies for
therapeutic development. Besides, we will develop
novel imaging analysis methods for small animal

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