The following are brief descriptions of the ongoing research projects in Dr. Wu's laboratory:

1. Reprogramming the glia cells to functional neurons for functional recovery after spinal cord injury (NIH R01NS111776). Severe morbidity and mortality are commonly associated with spinal cord injury (SCI). Human patients who survive SCI frequently live with paralysis and extremely reduced quality of life and productivity. SCI often results in a permanent loss of neurons and the disruption of neural circuits that are critical for normal motor, sensory, and autonomic function. It is crucial to replenish the lost neurons and reconstruct the broken neural circuits for functional recovery. Unlike some other tissues or organs in the body, such as skin and liver, which can undergo self-repair through proliferation of endogenous stem or somatic cells, adult spinal cord exhibits minimal regenerative capacity. We employ a novel strategy to reprogram endogenous reactive glial cells to mature neurons for functional recovery after SCI. Glial cells are abundant and ubiquitously distributed in the adult spinal cord. They become reactive, proliferate, and form glial scars in response to damage, and play critical roles in modulating tissue damage and repair after injury. Reprogramming reactive glial cells to neurons at the injury site will reduce local glial scar formation and enhance establishment of new neural circuit resulting in functional recovery.

2. A polypharmacoligical strategy to promote regeneration and recovery of function after cervical spinal cord injury (Indiana Department of Health’s Indiana Spinal Cord Injury Research Grant, ISDH58180). The pathways that convey the signals from the brain to the spinal cord are called supraspinal tracts. Among all supraspinal tracts, the corticospinal tract (CST) is the most influential pathway for voluntary movement of arms and hands in humans. Compared to other supraspinal tracts, the CST shows very limited plastic responses to traumatic SCI. Kinases play a critical role in cell processes including axon regeneration. Recently, we have shown that specifically targeting the mTOR substrate S6 Kinase 1 (S6K1) using the compound PF-4708671 (PF) promoted robust CST axonal regeneration across and beyond a C5 dorsal hemisection (C5-DH), accompanied by significant forelimb functional recoveries. Using a combination of phenotypic screening of primary neurons, biochemical profiling, information theory, and machine learning, we have discovered a top “hit” KI (RO0480500- 002; RO48), affecting “multi-targets”, so-called polypharmacology, that appears to be more effective to modulate intrinsic neuronal growth, as compared to the selective single kinase inhibitors (KIs, such as S6K1 inhibitor PF) and the weak multi-target KIs (such as Y-27562that has a strong effect only on ROCK and a weak effect on PKG and PKX). This RO48 compound was selected from the screening of 1600 kinase inhibitors (KIs); it strongly inhibits 5 important targets that synergistically modulate axon outgrowth.

3. Transhemispheric cortex remodeling promotes forelimb recovery after cervical spinal cord injury. Understanding the reorganization of neural circuits spared after spinal cord injury in the motor cortex and spinal cord would provide insight for developing therapeutics. Using optogenetic mapping we demonstrate a transhemispheric recruitment of neural circuits in the contralateral cortical M1/M2 area to improve the impaired forelimb function after a cervical  5 right-sided hemisection in mice, a model mimicking the human Brown-Séquard syndrome. This cortical reorganization can be elicited by a selective cortical optogenetic neuromodulation paradigm. Areas of whisker, jaw, and neck, together with the rostral forelimb area, on the motor cortex ipsilateral to the lesion are engaged to control the ipsilesional forelimb in both stimulation and non-stimulation groups. However, significant functional benefits are only seen in the stimulation group. Specific neuromodulation of the cortical neural circuits induces massive neural reorganization both in the motor cortex and spinal cord, constructing an alternative motor pathway in restoring impaired forelimb function.