This project will focus on the role of chemokines in modulating neuronal cell intracellular calcium signaling and excitability as a model for neurological dysfunction in HIV-1 infection. The hypothesis is that HIV-1 infection in the CNS induces release of soluble chemokines (IP-10, RANTES, MIP-1 alpha, IL-8) which bind neuronal chemokine receptors and activate signal transduction pathways that subserve normal neuronal cell responses to neuroeffector molecules. This may involve both short-term and long-term activation of MAP kinase. The result may be impairment of normal physiological responses in neurons, resulting in pathological dysfunction. The investigator will utilize rodent primary mixed hippocampal cultures from wild-type as well as selected transgenic animals provided to address four specific aims: 1) to determine the sensitivity and response of cultured rodent hippocampal neurons to acutely applied chemokines; 2) to identify the signaling pathways involved in neuronal chemokine receptor activation; 3) to determine whether acute chemokine exposure alters neuronal responsiveness to glutamate; and 4) to determine the effects of chronic chemokine exposure on neuronal and astrocytic electrophysiological responses. The overall design will address effects of both acute and chronic chemokine exposure on neuronal cell function and will include examination of two distinct classes of neurons, excitatory glutamatergic and inhibitory GABAergic neurons.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH063712-05
Application #
6846331
Study Section
Special Emphasis Panel (ZMH1-BRB-T (01))
Program Officer
Joseph, Jeymohan
Project Start
2001-03-01
Project End
2007-02-28
Budget Start
2005-03-01
Budget End
2007-02-28
Support Year
5
Fiscal Year
2005
Total Cost
$409,651
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Gruol, Donna L (2015) IL-6 regulation of synaptic function in the CNS. Neuropharmacology 96:42-54
Cho, Jungsook; Nelson, Thomas E; Bajova, Hilda et al. (2009) Chronic CXCL10 alters neuronal properties in rat hippocampal culture. J Neuroimmunol 207:92-100
Bajova, Hilda; Nelson, Thomas E; Gruol, Donna L (2008) Chronic CXCL10 alters the level of activated ERK1/2 and transcriptional factors CREB and NF-kappaB in hippocampal neuronal cell culture. J Neuroimmunol 195:36-46
Cho, Jungsook; Gruol, Donna L (2008) The chemokine CCL2 activates p38 mitogen-activated protein kinase pathway in cultured rat hippocampal cells. J Neuroimmunol 199:94-103
Vereyken, Elly J F; Bajova, Hilda; Chow, Stephine et al. (2007) Chronic interleukin-6 alters the level of synaptic proteins in hippocampus in culture and in vivo. Eur J Neurosci 25:3605-16
Gruol, Donna L; Nelson, Thomas E (2005) Purkinje neuron physiology is altered by the inflammatory factor interleukin-6. Cerebellum 4:198-205
Rempel, J D; Quina, L A; Blakely-Gonzales, P K et al. (2005) Viral induction of central nervous system innate immune responses. J Virol 79:4369-81
Nelson, Thomas E; Netzeband, Jeffrey G; Gruol, Donna L (2004) Chronic interleukin-6 exposure alters metabotropic glutamate receptor-activated calcium signalling in cerebellar Purkinje neurons. Eur J Neurosci 20:2387-400
Conroy, Shannon M; Nguyen, Vi; Quina, Lely A et al. (2004) Interleukin-6 produces neuronal loss in developing cerebellar granule neuron cultures. J Neuroimmunol 155:43-54
Nelson, Thomas E; Gruol, Donna L (2004) The chemokine CXCL10 modulates excitatory activity and intracellular calcium signaling in cultured hippocampal neurons. J Neuroimmunol 156:74-87

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