This mentored research program is designed to develop the candidate's cognitive, technical, and interpretive skills to a sufficient degree that he will become an independent investigator. This will be done through hands-on experience in the laboratory, additional course work, manuscript and grant preparation, presentations at relevant national meetings, and interactions with other basic scientists. Through the additional training he receives from his mentor, while conducting his own original research as outlined in this proposal, the candidate hopes to transition his line of investigation smoothly to funding at the R01 level. ? ? Central to the concept of immunotherapy is the notion that cancer cells have antigens that the immune system may recognize as foreign and subsequently destroy. T cells of the adaptive immune system would seem to be ideal for this task, but through systems employing model tumor antigens it is becoming apparent that T cells may actually be down-regulated or rendered tolerant after encountering tumor antigens. This process appears to be mediated by professional antigen-presenting cells (APCs) and to occur in much the same way that T cells are naturally rendered tolerant to normal antigens expressed in peripheral tissues of the body. For this reason most current vaccination strategies are now focusing on up-regulating the APC or creating a local milieu that leads to priming rather than tolerance. ? ? Using a model system of spontaneously arising osteosarcoma in which transgenic mice express the T antigen of SV40 under an alpha-amylase promoter, the candidate is able to track CD8+ T cells that recognize a distinct foreign epitope of the T antigen and observe them to be rendered tolerant in response to the tumor antigen. He now proposes to 1) further investigate the mechanism of this immunologic tolerance, 2) to change this tolerance to priming by up-regulating the APC, and 3) to study the differences in tumor antigen presentation that lead to tolerance versus priming. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08CA100094-05
Application #
7457696
Study Section
Subcommittee G - Education (NCI)
Program Officer
Myrick, Dorkina C
Project Start
2004-07-01
Project End
2010-06-30
Budget Start
2008-07-01
Budget End
2010-06-30
Support Year
5
Fiscal Year
2008
Total Cost
$135,270
Indirect Cost
Name
Pennsylvania State University
Department
Surgery
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
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