Immunological synapses are the recently characterized microanatomical structures that underlie immune cellular interactions. Establishment of immunological synapses between CTLs and infected or malignant astrocytes precedes the elimination of these astrocytes from the brain. How individual CTL target cells respond to T cell attack remains poorly understood. We have evidence suggesting that infected astrocytes respond in an active manner to the T cell attack. Our data suggests that target infected astrocytes change from multipolar to unipolar cells, i.e. they adopt a novel polarized phenotype that appears to include a reorganization of the cytoskeleton and intracellular organelles. We will test whether this active cellular reorganization could influence the ultimate outcome of the T cell attack, e.g. death or survival of infected astrocytes. In this application we will test the hypothesis that both infected astrocytes and tumor glioma cells respond in an active manner to T cell attack, and that this response is induced by a T cell-dependent activation of a Rho-GTPase signaling pathway. We will study the astrocyte responses to T cell attack in vivo and in vitro, and analyze the molecular signaling pathways underlying these responses. We believe that understanding the cellular and molecular mechanisms by which infected and malignant astrocytes respond to T cell attack should lead to better ways to eliminate neurological viral infections and brain tumors, enhance therapeutic transgene expression from gene therapy viral vectors, or protect the brain from autoimmune attack. To do so, we propose to explore the cellular and molecular basis of glial cell responses to immune attack both in vivo and in vitro in three Specific Aims.
Specific Aim 1 will test the hypothesis that formation of immunological synapses leads to the polarization of infected astrocytes and that this is dependent on the activation of a Rho-GTPase pathway;
Specific Aim 2 will test whether CTL signaling at mature immunological synapses in vivo between anti-viral T cells and infected astrocytes effectively leads to the death of infected astrocytes, or whether astrocytes can withstand such an attack;
and Specific Aim 3 will test the hypothesis that the effects of anti- tumor T cells on glioma cells are mediated through the formation of immunological synapses.

Public Health Relevance

Immunological synapses form in vivo between antiviral CTLs, and virally infected or malignant astrocytes causing a reorganization of their cellular structure. We believe this response influences the ultimate outcome of the T cell attack, e.g. death or survival of infected or tumor glial cells. We believe that understanding the cellular and molecular mechanisms by which infected and malignant astrocytes respond to T cell attack should lead to better ways of eliminating neurological viral infections and brain tumors, enhance therapeutic transgene expression from gene therapy viral vectors, or protect the brain in cases of autoimmune attack.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS061107-06
Application #
8338447
Study Section
Special Emphasis Panel (ZRG1-MDCN-M (02))
Program Officer
Fountain, Jane W
Project Start
2008-08-15
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
6
Fiscal Year
2012
Total Cost
$333,353
Indirect Cost
$118,978
Name
University of Michigan Ann Arbor
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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