RESEARCH KEY WORD：CNS micro-environment inflammation The protection and regeneration of neuron

Research Interest: The improvement of inflammatory micro-environment in CNS and the treatment of inflammation-related CNS disease

TEACHING:

Taking the teaching mission of human systemic anatomy and human regional anatomy for chinese and foreign (taught in English) undergraduate students. 300 class hour/per year.

【EDUCATION AND PROFESSIONAL EXPERIENCE】

07/2003-present:  (Assistant Professor:  Department of anatomy, Zhejiang University, school of medicine, Zhejiang)

Research direction:

1. Multiple sclerosis (MS) is a chronic neurological disorder that affects the central nervous system (CNS), and results in CNS inflammation and damage to myelin. In this study, we examined the possible synergistic effects of C16, angiopoietin-1 (Ang-1) and regeneration gene protein 2 (Reg-2) in alleviating inflammation in an acute experimental autoimmune encephalomyelitis (EAE) model. We employed multiple histological, morphological and iconographic assays to examine the effect of those drugs on disease onset, clinical scores and behavioral deficits. Our results demonstrated that triple combination therapy was more efficient than the monotherapy in EAE treatment. The triple therapy significantly delayed the onset of motor symptoms, reduced disease severity, attenuated inflammatory cell infiltration and suppressed the secretion of proinflammatory cytokines. Additionally, treatment increased anti-inflammatory cytokines expression, inhibited reactive astrocytes proliferation, reduced demyelination and axonal loss, and finally reduced the neural death. Specifically, Reg-2 administration rescued oligodendrocytes and neuronal axons mainly by direct neurotrophic effects, while C16+Ang-1 (C+A) mainly improved the inflammatory milieu. In conclusion, our study suggests a possible synergistic effect through targeting a variety of pathways in relieving the clinical symptoms of inflammation in acute EAE model. Therefore, using molecules that target different molecular pathways can be beneficial for exploring novel therapeutic approaches for MS treatment.

2. Placenta-derived mesenchymal stem cells (PMSCs) have emerged as an attractive source of MSCs for their lack of ethical issues, non-invasive access, and abundant yield. Transplanted PMSCs have been shown to produce neuroprotective effects similar to those of embryonic MSCs for ameliorating inflammation and neurological dysfunction in experimental autoimmune encephalomyelitis (EAE). However, inflammatory cell invasion into the grafts negatively impacts the survival and efficacy of the transplanted cells. Both angiopoietin-1 (Ang-1), an endothelial growth factor important in vascular development, and C16, a synthetic peptide that competitively binds avb3 and avb1 integrins on endothelial cells, have been shown to inhibit leukocyte transmigration. In this study, we investigated the effects of intravenous administration of C16 and Ang-1 on the efficacy of PMSC transplantation in a rat model of EAE. We found that, compared with PMSCs alone, treatment with PMSCs along with intravenous C16 and Ang-1 was more effective at ameliorating demyelination/neuronal loss and neurological dysfunction in the rat EAE model. The combinatorial treatment also demonstrated improved efficacy at reducing inflammatory cell infiltration, perivascular edema, and reactive astrogliosis. Mechanistic studies revealed that intravenous C16 and Ang-1 increased PMSC engraftment in the central nervous system and promoted expression of the neurotropic proteins brain-derived neurotrophic factor, growth-associated protein 43, and p75 neurotrophin receptor as well as the neuronal-glial lineage markers neurofilament protein 200 and myelin basic protein in the engrafted PMSCs.

3. Neuromyelitis optica (NMO) is an autoimmune inflammatory disease that selectively targets the optic nerves and spinal cord, leading to blindness and paralysis. Since NMO patients often present demyelinating lesions in the central nervous system (CNS), it has long been considered as a variant of multiple sclerosis (MS); however, recent data suggest that its pathogenesis may be different. Worldwide, the prevalence of NMO is far lower than that of MS, but NMO is more common in Asian populations. NMO has a worse outcome than MS, with frequent and early relapses. The pathophysiological processes of NMO remain to be revealed and require the testing of different therapies.

07/2006-07/2008:  (Postdoctoral Fellow: Kentucky Spinal Cord Injury Research Center, Louisville, KY, USA.

Supervisor: Prof. Theo Hagg (the Chair of the Department of Biomedical Sciences, the College of Medicine, East Tennessee State University)

Research direction:

Rescuing vasculature with intravenous angiopoietin-1 and ανβ3 integrin peptide is protective after spinal cord injury

Integrin ανβ3 was also shown to modulate leukocyte adhesion into intercellular adhesion molecule-1(ICAM-1) and enable leukocytes to migrate effectively across the endothelium. The synthetic C16 peptide (KAFDITYVRLKF), representing a functional laminin domain, may selectively bind to avb3 integrin, interfere with a leukocyte ligand required for transmigration and competitively block transmigration of leukocytes attempting to enter the CNS. Our studies have suggested that C16 application could reduce transendothelial migration of the C8166-CD4 lymphoblast cells, and alleviated extensive CNS infiltration of leukocytes and macrophages. Most importantly, C16 peptide is not an immune-suppressant and does not affect systemic leukocyte counts. Angiopoietin-1 through the Tie2 receptor, and other ligands through ανβ3 integrin, promote endothelial cell survival during developmental or tumour angiogenesis.Angiopoietin-1 and C16 were combined and the effects were additive, resulting in almost complete functional recovery. These results identify ανβ3 integrin and the endothelial-selective angiopoietin-1 as vascular and inflammatory regulators that can be targeted in a clinically relevant manner for neuroprotection after central nervous system trauma.

09/2001-07/2003:  (Postdoctoral Fellow: Laboratory of Neurobiology, Shanghai Second Medical University(SSMU), Shanghai)

Supervisor: Prof. Xiaoming Xu (Visiting professor of SSMU, Department of Neurological Surgery, Kentucky Spinal Cord Injury Research Center, University of Louisville. USA)

Research direction:

1 .Expression and functional analysis of Annexin II,V in spinal cord traverse model.

2. Expression and functional analysis of HB-GAM (heparin-binding growth associated molecules) in spinal cord traverse model.

Using cDNA microarray, western blot, immunohistochemistry, immunofluorescence double staining methods, we have gotten the expression change map of the RAG-1 during the developmental different stage in murine central nerve system.

 Using RT-PCR, morphology methods and behavioral testing of animals, observing the change levels of several transmitter that is related to the learning capability, memory and synaptic plasticity in diabetic rats model induced by streptozotocin.

Based on previous results, we continue to perform the investigation of the effects of grafting the annexins proteins and stem cells into the injured spinal cord of animals, our results have showed that annexin II may be an effective therapeutic agent to reduce spinal cord secondary injury, promote axonal growth, improve functional recovery after a transection of the spinal cord in adult rats and have the beneficial effects to the implanted neural stem cells when be treated synchronously.

09/1998-07/2001:  (Ph.D. candidate: Department of Anatomy and Neurobiology, Sun Yat-Sen University, school of medicine, Guangzhou)Supervisor: Prof. Zhibin Yao (Department of Anatomy and Neurobiology, Sun Yat-Sen)

Research direction:

1. Study of cellular death mechanisms underlying spinal cord injury in adult rat spinal cord motor neurons. 

2. The effects of natural antioxidation new drug TA9902 on spinal motoneurons survival following spinal nerve roots avalusion.

We adopted multidisciplinary neurosciences method including gene cloning, DNA sequenceing, immunohistochemistry, immunoelectron microscope, mammalian cell culture, spinal cord injury model establishment to investigate the pathological changes of motoneuron’s function and morphology following spinal cord injury. Based on these results, we have extracted a natural antioxidation new drug TA9902 from plants and it showed distinct effects of antioxidation and scaverging free radicals, which can remarkably decrease the numbers of neurons death after spinal cord injury. Now this drug has begun to be used in clinic in china

09/1995-07/1998:  (M.S.: Department of Human Anatomy, Xinjiang University, school of medicine, Xinjiang)

Supervisor: Prof. Huazhong Guan (Department of Human Anatomy, Xinjiang University, school of medicine, Xinjiang)

Research direction:

Extraction and biological activity analysis of neurotrophic factors in motor neuron.