Neuroimmunology and Regenerative Therapy Laboratory

Neuroimmunology and Regenerative Therapy Laboratory

Collaborators
Research Goals
Funding
Techniques used in the laboratory
Personnel
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Dr. Zheng's Biographical Information 


Collaborators

Dr. Yong Zhao

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Research Goals

The Laboratory of Neurotoxicology is currently pursuing several investigative routes to elucidate the mechanism involved in HIV-1 Associated Dementia (HAD). These routes include:

  • Neurogenesis
  • Mononuclear phagocyte (MP) activation in the brain
  • HIV viral proteins and their neurotoxic effects and
  • Chemokines (chemical signals) released by neurons, astrocytes and MP and their direct consequences on the brain environment.

While these areas of research seem miles apart, they are actually quite linked. Studies have shown that neurogenesis plays an important role in the adult brain and can be stimulated by neuronal injury, physical exercise or stress.

HIV-infected and activated MP can release viral proteins and neurotoxins, including glutamate, that injure neighboring neurons. Upon injury, neurons release chemokines that recruit more MPs to the site of injury, to repair the injury and promote neurogenesis as well as, rid the site of cellular debris and viral proteins. Infected and activated MP then respond to the signals produced by neurons, releasing more neurotoxins, thereby creating more damage and beginning yet another vicious cycle of injury.

Therefore, by integrating studies of neuroscience, virology, immunology, biochemistry and receptor pharmacology to investigate these areas, the neuropathogenesis of HAD can be fully explored. The mission of our lab is to ultimately develop drugs that will selectively inhibit neurotoxin production and enhance neuronal repair in the brain. These studies will not only answer questions regarding HAD, but also other neurological diseases such as Alzheimer's disease.

The Laboratory of Neurotoxicology is divided into three groups whose goals are either focused on neural injury, neural repair or cell therapy.

Neuroimmunology Group
Group Leader: Yunlong Huang, PhD

Goal(s): To check the pathological characteristics of neuro-immune interactions in HAD. To examine HIV-1 replication within the CNS, and the potential modulating host factors, such as TRAIL, FOXO3a and glutaminase.

Background: In HAD, production of cytokines and chemokines has been detected resulting from viral infection and brain injury. Small damage caused by initial viral (HIV-1) infection could instigate a chronic inflammatory state in the CNS. Our group used brain tissues from HAD patients to identify the pathological factors. We used in vitro cultures of CNS cell types to model the inflammation and neuronal injury during HAD. A murine HIV-1 encephalitis model was developed to confirm the pathogenic factors in vivo.

Project Titles:

  • Glutaminase regulation and potential pathogenic role in HAD
  • Innate immune sense of HIV-1 in macrophages
  • TNFSF10 (TRAIL) regulation and neurotoxicity in HADTNFSF10 (TRAIL) and type I interferon in the innate control of HIV-1 in macrophages
  • Microglia neurotoxicity and the glutaminase link in HAD
  • microRNA regulation and impact in HIV-1-infected macrophages
  • HIV-1 Clade diversity and macrophage-mediated neurotoxicity in HIV-1 dementia

Neural Stem Cells and Brain Inflammation Group
Group Leader: Hui Peng, MD

Goal(s): To study the effect of brain inflammatory factors (chemokines and cytokines) on neural stem cell function in HAD.

Background: Active neurogenesis occurs throughout life and relies upon the proliferation, migration, and proper differentiation of neural stem/progenitor cells (NPCs). Diminished adult neurogenesis is considered a potential factor in the pathogenesis of neurodegenerative diseases, including HAD. By examining the effect of brain inflammatory factors on neural stem cell function, we will identify potential targets for therapeutic intervention for neurodegenerative diseases.

Project Titles:

  • HIV-1-infected and/or immune activated macrophage affects neural progenitor cell proliferation and differentiation
  • Cytokines induce astrogliogenesis through the STAT3 pathway
  • CXCL12 induces diverse signaling and function on neural progenitor cell through CXCR4 and CXCR7

Stem Cells and Cell Therapy Group
Group Leader: Changhai Tian, PhD

Goal(s): To generate and differentiate mouse and human induce pluripotent stem (iPS) cells, to establish the PD mouse model, and to further explore the application of iPS cells for cell therapy of PD.

Background: By reprogramming somatic cells to a pluripotent state, so-called iPS cells have been achieved by the introduction of transcription factors by different delivery systems. This discovery generated much excitement because of the potential therapeutic applications of these cells in developmental biology, regenerative medicine, and cancer biology.

Project Titles:

  • Comparison of different cell type-derived iPS cell lines
  • Directional differentiation of iPS cells
  • Establishment of PD model in mice with 6-OHDA and iPS cell therapy for PD

Research Programs

TRAIL and glutaminase: neurotoxic link in HIV Dementia
The goal of this project is to investigate the role of TRAIL and glutaminase mediated neuronal damage in HAD. Using primary human macrophage and neuronal culture systems, we propose to study the linkage between macrophage activation and neuronal dysfunction through TRAIL and glutaminase mediated mechanisms.

Neuronal chemokines and macrophage activation
This project investigates the regulation of neuronal chemokines in response to neuronal injury. Characteristics of neuronal chemokine mediated macrophage activation will be examined via state of the art gene array technology. The aim is to determine the expression and regulation of macrophage products after HIV-1 infection, neuronal chemokine mediated activation, or concurrent HIV infection and chemokine activation.

CXCR4, neurogenesis and HIV-1 associated Dementia
This project focuses on the role of neurogenesis during HIV-1 associated dementia (HAD). Specifically, the major goal of this project is to investigate the role of the chemokine receptor, CXCR4, in neurogenesis and its linkage to the pathogenesis of HAD. Using primary human macrophage and neural progenitor cell (NPC) culture system, we propose to study the possible mechanisms that underlie NPC recruitment, proliferation and differentiation in HAD. The effect of chemokines and other macrophage factors on NPC recruitment, proliferation and differentiation will be investigated.

Laboratory models for macrophage activation in neurodegenerative disorders
This project will develop laboratory assays that mimic brain macrophage activation and innate CNS immune responses in HAD and AD. We will use primary MP to determine the mechanisms for macrophage activation, to define signal transduction pathways for the regulation of inflammatory factors, and uncover the outcome of glial-inflammatory products for neuronal destruction. In addition, we will utilize sera and PBMC from AD and HAD patients followed prospectively to determine the validity and biological significance of our laboratory findings in regards to innate immunity and neurodegeneration. This project is a collaborative initiative involving multiple basic and clinical investigators within the department and UNMC.

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Funding

Neural immunity in HIV dementia
Project 1:
Mononuclear phagocytes, immunity and neural progenitor cells
PI: HE Gendelman; PI: J Zheng, Project 1, PI
NIH/NINDS
This project will investigate the role of mononuclear phagocytes and cytokines in the regulation of neural progenitor cells (NPC) migration, proliferation and differentiation. Cytokine mediated effect on NPC migration and differentiation and its associated signaling pathways such as TRAF, MAP kinase, NF-κB, inhibitory basic helix-loop-helix (bHLH) transcription factor Hes1 will be determined.

TRAIL and Glutaminase: Neurotoxic Link In HIV Dementia
PI: J. Zheng
NIH/NINDS
The major goals of this project are to investigate the role of TRAIL and glutaminase mediated neuronal injury in HIV-1 associated dementia (HAD). This proposal integrates disciplines of virology, immunology, and receptor pharmacology in a mechanistic study of HAD.

SDF-1 and neurogenesis in HIV-1 associated dementia
PI: J. Zheng
NIH/NINDS
The major goals of this project are to investigate the role of SDF-1 and CXCR4 mediated neuronal repair process in HIV-1 associated dementia.

HIV-1 Clade Diversity and Macrophage Mediated Neurotoxicity in HIV-1 Dementia
PI: J. Zheng
NIH/NIMH
The major goals of this project are to investigate the role of HIV-1 clade diversity and macrophage mediated neuronal injury in HIV-1 associated dementia.

Macrophages, Neuronal K+ Channels and HIV-1 Dementia
PI: H. Xiong; Co-I: J. Zheng
NIH/NINDS
This grant proposes to study the mechanisms underlying HIV-1-infected mononuclear phagocytes that affect neuronal synaptic transmission and plasticity and NMDA receptor functions

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Techniques used in the laboratory

Our laboratory integrates techniques in immunology, neuroscience, virology, receptor pharmacology, molecular biology and biochemistry to study the mechanisms involved in the neuropathogenesis of HIV-1 Associated Disorders (HAD).

  • Cell Culture
  • Real Time RT PCR
  • ChIP Assay
  • Western Blot
  • ELISA
  • siRNA
  • High Performance Liquid Chromatography
  • Immunostaining
  • Histology
  • Microscopy

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Personnel

Lenal_Bottoms

Lenal Bottoms
Support Staff

lenal.bottoms@unmc.edu

 

 Yuju Li Yuju Li
Research Associate
yuji.li@unmc.edu
 Yi Wang Yi Wang
Graduate Student
yi.wang@unmc.edu
 

Mary Cavell
APRDP Coordinator
mcavell@unmc.edu

 Hui Peng

Hui Peng, PhD
Assistant Professor
hpeng@unmc.edu

Yongziang Wang

Yongxiang Wang
Graduate Student
ywan1@unmc.edu


 

 Qiang Chen

Qiang Chen
Graduate Student
qche1@unmc.edu

Changhai Tian

Changhai Tian, PhD
Instructor
ctian@unmc.edu

Beiqing_Wu

Beiqing Wu
Graduate Student
beiqing.wu@unmc.edu

Yunlong Huang

Yunlong Huang, PhD
Instructor
yhuan1@unmc.edu

Zenghan_Tong2013 Zenghan Tong
Senior Research Associate
zenghan.tong@unmc.edu
Dongsheng Xu

Dongsheng Xu, MD
Instructor
dongsheng.xu@unmc.edu

         Yong Zhao

Yong Zhao, PhD
Assistant Professor
yongzhao@unmc.edu

Former Graduate Students and Post Doctoral Fellows

Robin Cotter Ph.D. Instructor, Phoenix College, Phoenix, AZ
Lisa Ryan M.D., Ph.D. 2002 Pediatrician, St. Louis, MO
Alicia Lopez M.S., 2002 Nurse practitioner, University of Arizona in Tucson
Yunlong Huang Ph.D., 2007 Instructor, University of Nebraska Medical Center, College of Medicine
Nathan Erdmann M.D., Ph.D., 2008 University of Alabama, Birmingham
Nicholas Paul Whitney Ph.D., 2009 Postdoctoral Fellow, University of Nebraska-Lincoln    
Ling Yi    
Agnes Constantino Ph.D., 2011 Intern UNeMED Corporation

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Return to Dr. Zheng's home page

Dr. Zheng's Biographical Information

Asian Pacific Rim Research Development Program

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