Neuronal Chemokines and Macrophage Activation

Project: Research project

Description

Brain mononuclear phagocyte (MP; macrophage and microglia) activation and neuronal injury are central features of HIV-1 encephalitis (HIVE), the pathological correlate of HIV-1-associated dementia (HAD). However, the pathways through which brain MP activation occurs and elicits neuronal dysfunction remains poorly understood. Recently, others and we demonstrated that neural injury can directly affect MP activation, through production of neuronal chemokines such as fractalkine (FKN). FKN is constitutively expressed on neurons and can be released in a soluble form. FKN can activate MP and induce cytokine secretion. Further, CSF levels of FKN are higher in HAD patients than in infected subjects without neurological disease. Thus, we hypothesize that MP recruitment and activation in HAD is regulated, in part, by FKN.
While it is acknowledged that MP secrete both neurotrophic and toxic factors following viral infection and activation, the signaling pathways which selectively regulate these processes remain to be elucidated. To this end, we propose that FKN-stimulation and HIV-1 infection of brain MP leads to the activation of multiple protein kinase pathways, such as the MAP kinases. Activation of these pathways result in neurotrophic and toxic factor dysregulation and ultimately neuronal compromise. Primary human macrophage, microglia and neuronal culture systems, combined with "state-of-the-art" human gene microarray technology, will be used to study how FKN mediates MP activation, affects intracellular signaling pathways, and regulates both neurotrophic and neurotoxic factor production. The determination of mechanisms involved in FKN-mediated MP activation and secretory factor production may assist in identification of potential targets for therapeutic intervention. This project unites with others in the program in seeking to determine how MP immunity affects the neurodegenerative process associated with HAD.
StatusFinished
Effective start/end date4/1/022/28/14

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $1,202,916.00
  • National Institutes of Health: $1,203,934.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $1,171,485.00
  • National Institutes of Health
  • National Institutes of Health: $1,139,991.00
  • National Institutes of Health: $1,164,241.00
  • National Institutes of Health
  • National Institutes of Health: $1,137,512.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $1,131,457.00
  • National Institutes of Health
  • National Institutes of Health: $91,840.00
  • National Institutes of Health: $1,176,000.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $1,176,000.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $1,203,933.00
  • National Institutes of Health

Fingerprint

HIV-1
AIDS Dementia Complex
Chemokine CX3CL1
Immunity
Dementia
Macrophages
Brain
Phagocytes
Proteomics
Blood-Brain Barrier
Microglia
Stem Cells
Macrophage Activation
Nerve Growth Factors
Chemokines
Neurosciences
Poisons
Neurodegenerative Diseases
Chemokine CXCL12
Therapeutics

ASJC

  • Medicine(all)
  • Neuroscience(all)