The primary research goal of this proposal is to understand the pathogenic mechanism of neuroimmunodegeneration (NID) induced by a mutant of the Moloney murine leukemia virus, ts1. As in HIV infection, ts1 infection of mice causes the direct killing of T cells and indirect killing of neurons. The latter is likely due to loss of essential support by the infected glial cells. The mechanism that leads to the apoptotic cell death and neuronal loss seen in HIV or ts1 infection are unclear. The viral envelope protein apparently plays an important role in both HIV - and ts1-mediated NID. A single amino acid substitution in the env gene of ts1 is responsible for inefficient transport of gPr80env from the endoplasmic reticulum (ER) to the Golgi apparatus. This mutation has also been correlated to ts1 ability to induce NID. In infected T cells and astrocytes the inefficient transport of ts1 gPr80env is particularly severe, resulting in accumulation of gPr80env in the ER. The working hypotheses are: (1) ER is the primary site where ts1 env-mediated apoptotic effects are initiated; (2) The ts1 envelope protein may interact with the plasma membrane and interfere with receptor signaling responsible for triggering apoptosis; and (3) ts1 may directly activate the ICE family of proteases to trigger apoptosis. The investigator proposes to characterize the mechanisms involved in T-cell and astrocyte death induced by ts1.
The specific aims are to: 1) Determine the mechanisms of gPr80env-mediated cell death; 2) identify the downstream factors possibly involved in ts1-mediated cell-death pathways; 3) Determine whether the ICE cell death pathway is utilized in ts1-mediated NID by evaluating clinical disease progression in ts1-infected ICE homozygous (-/-), heterozygous (+/-) and wild type (+/+) mice; 4) Determine the role of ICE in ts1-mediated indirect neuronal death; and 5) Determine whether overexpression of Bcl-2 in neurons can protect against ts1-induced neurodegeneration.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI028283-11
Application #
6170175
Study Section
Special Emphasis Panel (ZRG1-AARR-2 (01))
Program Officer
Plaeger, Susan F
Project Start
1988-12-01
Project End
2004-03-31
Budget Start
2000-04-01
Budget End
2001-03-31
Support Year
11
Fiscal Year
2000
Total Cost
$289,484
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Organized Research Units
DUNS #
001910777
City
Houston
State
TX
Country
United States
Zip Code
77030