This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Neural progenitor cells (NPC) are critical for maintenance of CNS homeostasis. These cells persist throughout life and replenish neurons, astrocytes and oligodendrocytes as needed through a process referred to as neurogenesis. In neurodegenerative disorders, this process appears to be dysfunctional since dead or injured neurons, astrocytes and oligodendrocytes are not replaced. HIV associated dementia (HAD) is one of these disorders that has aroused significant interest. Recently, we demonstrated that CXCR4, an important co-receptor for HIV-1, was more highly expressed on human NPC than other chemokine receptors, and was coupled to downstream signaling systems. The intrinsic CXCR4 ligand, stromal cell-derived factor 1 (SDF-1), released in response to neuronal injury and astrocyte activation was also elevated in cerebral spinal fluids of HAD patients compared to infected subjects without neurological disorders. Recent studies have also shown that SDF-1 is cleaved by activated matrix metalloproteinase-2 (MMP-2) to form the highly neurotoxic SDF-1 (5-67). MMP-2 is also highly expressed on HIV-1-infected mononuclear phagocytes (MP), which play a central role in HAD. Neurogenesis is an emerging field and its role in HAD is poorly understood. This proposal examines the hypothesis that while activated astrocytes and injured neurons produce elevated levels of SDF-1 that promote neurogenesis, proteolysis of SDF-1 by enzymes released from HIV-1-infected MP could lead to an impairment of SDF-1/CXCR4 mediated neurogenic responses and prove detrimental to CNS repair. Using a newly developed human NPC culture system, we propose to study the role of SDF-1 (production, modification and function) in neurogenesis. We will use molecular manipulations, including gene silencing, and in vitro assays that mimic brain MP activation and innate CNS immune responses that occur in HAD, to examine the mechanisms of SDF-1 regulation. The knowledge gained from elucidating the mechanisms by which SDF-1/CXCR4 interact in neurogenesis may open up new therapeutic strategies for treating not only HAD but other neurodegenerative disorders.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Exploratory Grants (P20)
Project #
5P20RR015635-09
Application #
7719942
Study Section
Special Emphasis Panel (ZRR1-RI-8 (01))
Project Start
2008-05-01
Project End
2009-04-30
Budget Start
2008-05-01
Budget End
2009-04-30
Support Year
9
Fiscal Year
2008
Total Cost
$284,022
Indirect Cost
Name
University of Nebraska Lincoln
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
555456995
City
Lincoln
State
NE
Country
United States
Zip Code
68588
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