Wei Wu, PhD

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. Modulation of lumbar motor circuitry after an above-level SCI and NT-3 gene therapy (NIH R01 NS103481). Spinal cord injury (SCI) is a severe medical problem experienced by humans with high mortality and long-term morbidity. Unfortunately, there has been no effective treatment available for SCI patients. The lumbar motoneurons (MNs) are the final common pathway for motor output to the hindlimbs. Any impairment of these MNs can cause hindlimb paralysis and muscle atrophy. When SCI occurs above the lumbar level, namely above-level injury, the lumbar MNs are not directly damaged by the trauma, but they undergo profound dendritic atrophy and synaptic stripping. While most SCI studies to date have focused on the regeneration or protection of the injured spinal cord at the injury site, few studies have explored how modulation of lumbar MN circuitry would affect pathological and functional consequences after an above-level SCI. Our goal is to develop a beneficial restorative treatment targeting lumbar MNs after an above-level SCI and to functionally dissect out how individual afferent pathways affect lumbar MN remodeling and functional recovery. In this application, we propose a central hypothesis that increasing local NT-3 levels at lumbar MN pools will stimulate the recruitment of spared axons from distinct afferent pathways and enhance their synaptic formation onto lumbar MNs. Thus, reestablishment of neural circuitry at the lumbar level forms the anatomical basis for hindlimb functional recovery after an above-level SCI. Accordingly, three specific aims are proposed to investigate the three major afferent pathways to influencing lumbar MNs function to determine their roles in NT- 3-mediated remodeling of lumbar motor circuitry and hindlimb recovery after a thoracic SCI. These pathways include the descending reticulospinal tracts (RetST), the descending propriospinal tracts (dPST), and the dorsal roots (DR) afferents. Once the functional role of each specific pathway is defined, we will used combinational approaches to target multiple pathways to maximize the treatment effect. This will be done u sing an adult mouse thoracic 9 (T9) contusive SCI model and an AAV2-NT-3 gene transfer approach to increase the level of NT-3 in MNs.

4. 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.