The final goal of our research is to develop novel treatments to achieve meaningful recovery of neurological functions for patients who have become disabled due to acute CNS injuries such as stroke and trauma.

 

Neurological functions are impaired frequently due to a disruption of axonal connections. For example, focal injuries at a few segments of the spinal cord can cause severe disabilities like paraplegia or quadriplegia, since neural connections between the brain and spinal motor centers can be severed by injuries with a diameter less than 1 cm. In old-aged citizens, multiple ischemic injuries to the white matter are a frequent cause of cognitive decline and gait abnormality, which are typified in the subcortical vascular dementia. This is also due to a disruption of cortico-cortical and/or cortico-subcortical neural circuits.

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Therefore, we propose that regeneration of severed axons or minimizing degeneration of axons and myelin sheath can ensure clinically meaningful functional recovery. We have begun three projects to accomplish axon regeneration and to attenuate ischemic white matter degeneration, which are illustrated below.

 

To these ends, we are employing interdisciplinary modalities ranging from basic biochemical tools, primary neural and stem cell cultures, mouse genetics, in vivo gene delivery, axon tracing, and functional behavioral assessments. We are being constantly spurred by rapid progresses in concepts and experiment tool in the field of connectomics, the study of neural connections. We wish you to become interested in “Reverse Connectomics”, in which RePairing injured neural connections relies on the blueprint created by works from the connectomics.

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1) To promote axon regeneration using pro-regenerative macrophage

Severed axons do not spontaneously regenerate partly because mature neurons do not possess intrinsic capacity to mount sustained axon growth. We hypothesize that one of the reasons for the lack of intrinsic growth capacity is that mature neurons do not receive external signals to maintain growth state. We have demonstrated that in PNS, axonal injury elicits neuron-macrophage interaction leading enhanced axon growth capacity. We are now testing our hypothesis activating or mobilizing perineural macrophages with a proregenerative phenotype could support neurons to maintain genetic programs for axonal growth.

References)

  • Role of Myc proto-oncogene as a transcriptional hub to regulate the expression of regeneration-associated genes following preconditioning peripheral nerve injury. J Neurosci. 2021

  • CCL2 Mediates Neuron-Macrophage Interactions to Drive Proregenerative Macrophage Activation Following Preconditioning Injury. J Neurosci. 2015

  • Contribution of macrophages to enhanced regenerative capacity of dorsal root ganglia sensory neurons by conditioning injury. J Neurosci. 2013 

 

2) To rebuild neural circuit using neural stem cells

Even though we might be able to induce regeneration of severed axons, it would be extremely challenging to achieve axon growth over a long distance. For example, injured corticospinal axons in the cervical area should grow almost 1 meter to reach their original synaptic targets in the lumbar spinal cord. Therefore, it would be more efficient to have sort of relay neurons in the course of the axonal path, which then can grow a shorter distance to the targets. We are aiming at devising an optimal strategy to provide neurons derived from transplanted neural stem cells to meet this goal. We are developing ways to improve survival of transplanted neural stem cells and to promote axonal growth of neural stem cell-derived neurons. One prerequisite for a good extent of neural stem cell survival is for transplanted neural stem cells to get integrated with host ECM, rather than fluid-filled cystic lesions frequently observed in CNS trauma. We have demonstrated possibility that injectable hydrogel can accommodate highly variable lesion geometry and preventing cavitation by promoting ECM remodeling. We are looking to find a good combinatorial approach centered on injectable hydrogel to enhance survival and axon growth of transplanted neural stem cells.

 

References)

  • An injectable hydrogel enhances tissue repair after spinal cord injury by promoting extracellular matrix remodeling. Nat Commun. 2017 

  • Survival of neural stem cell grafts in the lesioned spinal cord is enhanced by a combination of treadmill locomotor training via insulin-like growth factor-1 signaling. J Neurosci. 2014

 

3) To protect white matter from ischemic injuries

Ischemic injuries to the white matter lead to axonal degeneration and demyelination. Although the advent of MR imaging technology revealed that white matter ischemia is highly prevalent in old ages, it is still unclear how ischemia can lead to degeneration of oligodendrocytes and demyelination. We found that ischemic injuries elicit innate inflammation signaling through Toll-like receptor 2 (TLR2) and the TLR2 and its downstream signaling are intricately involved in oligodendrocyte degeneration. An important hurdle for this line of research is a lack of an adequate animal model for ischemic white matter degeneration. Developing animal models for white matter stroke with consistent and prominent pathology would not only allow delving into pathomechanisms of ischemic white matter degeneration but also provide an in vivo platform in which we can test novel molecules regulating inflammatory cascades to attenuate white matter ischemia and accompanying cognitive deficits.

 

References)

  • High-mobility group box-1 as an autocrine trophic factor in white matter stroke. Proc Natl Acad Sci U S A. 2017

  • Role of toll-like receptor 2 in ischemic demyelination and oligodendrocyte death. Neurobiol Aging. 2014