Significance
I. Development of nucleic acid enzymes for gene function analysis and drug target validation
Recent progress in understanding how gene products interact in the control of cell proliferation and differentiation has engendered high hopes for the rational design of specific therapeutic strategies aimed at the control of proliferative disorders, such as cancer. Despite this expectation, successes have been rare. This may reflect (1) our incomplete understanding of the extra- and/or intracellular signalling pathways that control cell proliferation, and (2) the lack of anti-gene strategies for dissecting gene function and drug target validation. At present, there are several genetic approaches being pursued to affect gene function. Unique among these approaches, is the use ribozymes and small interfering RNAs (siRNAs). Broadly speaking we are interested in uncovering novel signal pathways responsible for tumour cell proliferation, metastasis and angiogenesis via the use of small interfering RNAs, and the identification of human genes whose expression is regulated by naturally occurring antisense RNA. Notably, loss of post-transcriptional gene silencing mediated by endogenous antisense RNAs may initiate and/or perpetuate diseases such as cancer.
II. Display methods
The possibility of selecting ligands from large random peptides or protein libraries has raised an important interest for defining antibody and T cell specificities. Using this strategy, we have shown for the first time that phage display peptide libraries can trace specific immune responses in patients with autoimmune diseases. Thus, immune responses, imprinted in patient’s sera as specific antibodies can be decoded by the technology. One important application of this strategy would be the study of the immune responses in patients with cancer, since it has been difficult to identify immunogenic antigens capable of inducing immune responses in patients to a threshold required for tumour rejection. In this respect, we have found that combination of phage display technology and an immunoscreening approach can probe specific immune response against tumour cells. The subset of patient antibody-specific lead peptides may have utility for the identification of novel molecular markers and targets for diagnostic and therapeutic intervention.Moreover, the expression of tumour antigens on either the surface of phages, or bacteria, or viruses may facilitate the design of cancer vaccines.
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