NASA Scientific and Technical Aerospace Reports

20040111528 Johns Hopkins Univ., Baltimore, MD
Molecular Mechanisms of Bacterial Superantigen Function
Sadegh-Nasseri, Scheherazade; Jul. 2004; 24 pp.; In English
Contract(s)/Grant(s): DAMD17-00-1-0671
Report No.(s): AD-A425535; No Copyright; Avail: CASI; A03, Hardcopy
Superantigens (SAGS) are a group of immunostimulatory and disease associated proteins of bacterial or viral origin that
bind to MHC molecules and certain T cell receptor (TCR) Vb domains and can result in systemic shock and death. Rational
design of strategies for prevention or treatments of such diseases may only be possible if we have insights into the mechanisms
of T cell activation by SEs. During this grant, we cloned and expressed a human TCR gene in bacculovirus expression system.
We demonstrated that the- expressed TCR was properly folded and was functional. We also produced soluble human MHC
class II HLA- DR1 and studied the kinetics of its interactions with TCR and different Superantigens by several biochemical
and biophysical methods. We measured the kinetics of interactions between SAGs and HLA- DRl and the formation of ternary
and guaternary complexes between TCR, DRl, peptides, and SAGs. We discovered that SAGs such as SEA and SEE bind
HLA-DRl or HLA-DRl in complex with peptide and enforce rigidity in the groove of MHC II that prevents conformational
changes necessary for association with a new peptide, or dissociation of the bound peptide. These observations change the
conventional understanding of SAGs/ MHC by TCR and helps in clever designs of therapeutics.
DTIC
Antigens; Bacteria; Lymphocytes
20040111530 Washington Univ., Seattle, WA
Genetic Factors that Affect Tumorigenesis in NF1
Stephens, Karen; Nov. 2003; 157 pp.; In English; Original contains color illustrations
Contract(s)/Grant(s): DAMD17-00-1-0542
Report No.(s): AD-A425539; No Copyright; Avail: CASI; A08, Hardcopy
Neurofibromatosis type 1 affects 1/4000 individuals worldwide and predisposes to the growth of both benign and
malignant tumors. Our research is focused on NFl microdeletions that are associated with an early onset, and subsequent heavy
burden, of cutaneous neurofibromas. We reported that the deletions arise by homologous recombination between 51 kb repeat
elements (NR1REP) that flank the NF1 gene. We identified recombination hotspots where 69% of NF1 microdeletions occur
and developed robust and sensitive assays to detect microdeletions in a patient blood sample. We analyzed the structure and
sequence of four NR1REP paralogs in the genome and described sequence features that may mediate recombination at these
sites. We developed new quantitative PCR assays that will detect nonrecurrent NFl microdeletions that occur either in the
germline or in somatic tissues including tumors. Our data make substantial contributions to understanding how NFl
microdeletions occur, create resources to inquire whether some individuals are more susceptible, and which deleted sequences
may cause the severe tumor phenotype of these patients.
DTIC
Cancer; Genetics; Recombination Reactions
20040111531 Texas Univ., Houston, TX
P202 AS A Potential Therapeutic Gene for Breast Cancer
Hung, Mien-Chie; Apr. 2004; 26 pp.; In English
Contract(s)/Grant(s): DAMD17-00-1-0312
Report No.(s): AD-A425540; No Copyright; Avail: CASI; A03, Hardcopy
The main goal of this proposal is to study the anti-tumor activity of p202 and its application in a breast cancer model
system. Three specific aims are 1) To determine the effects of p2O2 on the sensitivity of breast cancer%%cells to anticancer
agents; 2) To test the anti-tumor activity of p202 in breast cancer cells using preclinical gene therapy strategies in an orthotopic
breast cancer animal model; and 3) To evaluate the therapeutic efficacy of p202 gene therapy in combination with other
anti-cancer agents in an orthotopic breast cancer animal model. We have completed the first two aims in the funding period.
However, In an attempt to develop the p202 gene as a therapeutic gene for human clinical trials, we initiated a communication
with FDA and were told that the p202 gene is of mouse origin and it is not favorable for human clinical trials. Hence, we turn
our attention to the human 200 family members in a hope to identify a human gene associates with a strong anti-cancer activity
as p202 does. To this end, we found that growth arrest of AIM2 is comparable to that of p202. Therefore, in the current status,
we intend to further characterize the anti-cancer activity and therapeutic efficacy of AIM2 gene in vitro and in vivo, and to
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