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Principal Investigator: Dr. John Parker
Contact Information: E-mail: jsp7@cornell.edu - Phone: 607-256-5626
Sponsor: Burroughs Wellcome
Grant Number: N/A
Title: Reovirus-Induced Apoptosis: The Role of the Viral Outer Capsid Protein Mu1
Annual Direct Cost: $80,000
Project Period: 07/01/05-06/30/10
Reoviruses are non-pathogenic human viruses that have the unexpected capacity to target and selectively kill Ras-transformed cancer cells by inducing apoptosis, while relatively sparing untransformed cells. Because of this reoviruses are currently being evaluated as anti-cancer therapeutic agents. Although, much has been learned about the apoptotic pathways and signaling molecules that are activated following reovirus infection, the molecular details of how specific reovirus proteins initiate apoptosis remains unclear. Early genetic studies identified the s1- encoding S1 and µ1-encoding M2 viral genes as determinants of increased apoptosis for particular reovirus strains. The s1 and µ1 proteins are believed to be directly responsible for inducing apoptosis. Most attention has focused on the role of the s1, the viral attachment protein, in apoptosis induction. In this proposal I focus on the proapoptotic role of µ1, a viral outer capsid protein responsible for membrane penetration during cell entry. I hypothesize that the reovirus µ1 protein plays a major role in the induction of apoptosis during viral replication. This hypothesis is based on my preliminary findings that µ1 induces apoptosis when expressed alone in cells and published evidence that the gene encoding µ1 is a determinant of reovirus-induced apoptosis. This hypothesis will be addressed with three specific aims:
1. To identify the specific region(s) of the µ1 protein that is responsible for inducing apoptosis.
2. To determine the mechanism(s) by which the µ1 protein induces apoptosis in transfected cells and to assess its contribution to apoptosis induction in infected cells during viral replication.
3. To identify the specific cellular apoptotic pathways(s) activated by the µ1 protein.
These studies should provide significant insights into the mechanisms of reovirus-induced apoptosis and may lead to improved applications of reoviruses as anti-tumor agents.
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