Human cytomegalovirus (CMV) causes devastating neurological disease in congenitally infected newborns. Many CMV gene products function to modulate and evade the host immune response to infection. CMV UL37x1 encodes a viral mitochondrial inhibitor of apoptosis (vMIA) that may be able to prevent or delay an apoptotic process in infected host cells. vMIA has been shown to block extrinsic and intrinsic death signals in the host cell, preventing mitochondrial membrane permeabilization and cytochrome c release. However, the mechanism of vMIA action is not known and it has no homology to cellular Bcl-2 family members, which have been shown to regulate cellular apoptotic signaling at mitochondria. We propose to characterize the mechanism of vMIA inhibition of apoptosis by mapping the amino acids required, elucidating cellular binding partners, and demonstrating the functional interaction of vMIA and its binding partners. Following this, we will determine the requirement for vMIA function in CMV replication by testing complementation of vMIA-deficient CMV infection with wild-type and mutated forms of vMIA, as well as other cellular or viral antiapoptotic proteins. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
1F30NS051109-01
Application #
6887616
Study Section
Special Emphasis Panel (ZNS1-SRB-S (06))
Program Officer
Nunn, Michael
Project Start
2004-12-21
Project End
2005-11-20
Budget Start
2004-12-21
Budget End
2005-11-20
Support Year
1
Fiscal Year
2005
Total Cost
$27,646
Indirect Cost
Name
Stanford University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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Smith, Geoffrey B; Mocarski, Edward S (2005) Contribution of GADD45 family members to cell death suppression by cellular Bcl-xL and cytomegalovirus vMIA. J Virol 79:14923-32
McCormick, A Louise; Meiering, Christopher D; Smith, Geoffrey B et al. (2005) Mitochondrial cell death suppressors carried by human and murine cytomegalovirus confer resistance to proteasome inhibitor-induced apoptosis. J Virol 79:12205-17