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Novel genes and methods that modulate apoptosis

a technology of apoptosis and genes, applied in the field of new genes and methods that modulate apoptosis, can solve the problems of hindering the screening of potential therapeutics, lack of understanding, and negatively interfering with the host process, and achieve the effect of reducing the number of cells

Inactive Publication Date: 2004-06-24
BOSTON MEDICAL CENTER INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent is about identifying and testing new substances that can activate or inhibit the process of cell death called FAIM activation. The invention also includes methods for measuring the degree of cell death and for designing drugs and gene therapies to modify the programmed cell death process. The patent also discusses the role of CD40 and Fas in regulating B cell death and how the invention can be used to protect B cells from Fas-mediated apoptosis. Overall, the patent provides new tools for research and development of treatments for cell death-related diseases.

Problems solved by technology

The screening of potential therapeutics has been hindered by both a lack of understanding of the physiological basis of cell death and by a dearth of reagents specific for critical points in the cell death signaling pathways.
It may, in effect, function as a diminisher of natural gene function if the natural gene is present and functional in the host into which the lof oligonucleotide was transfected, or may negatively interfere with processes in the host if the natural gene is not present or is non-functional.

Method used

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  • Novel genes and methods that modulate apoptosis
  • Novel genes and methods that modulate apoptosis
  • Novel genes and methods that modulate apoptosis

Examples

Experimental program
Comparison scheme
Effect test

experiment i

[0119] In previous work we showed that B cell treatment with anti-Ig for only the final 1-12 hours of a 48 hour culture with CD40L produced a time-dependent increase in Fas-resistance that was abrogated by cycloheximide (Foote et al. "Intracellular signaling for inducible antigen receptor-mediated Fas resistance in B cells" J. Immunol. 157:1878-1885, 1996). Additional experiments demonstrated that the induction of Fas-resistance in CD40L-stimulated B cells by anti-Ig treatment for 6 hours was completely blocked by the addition of actinomycin D (data not shown). These results strongly suggest that transcriptional activation and gene expression are required for the receptor-specific induction of the Fas-resistant state. For this reason, genes that oppose Fas-mediated apoptosis might be captured by identifying transcripts expressed uniquely in Fas-resistant B cells.

[0120] To identify genes expressed coordinately with the induction of Fas-resistance we employed a differential display st...

experiment ii

[0121] Using a radiolabeled probe generated by PCR, a murine thymic cDNA library was screened and the DNA from positive plaques sequenced. A number of overlapping clones were identified whose consensus sequence was approximately 1.2 kb, consistent with the expression data described above. Subsequently a full-length clone was identified that contained an in-frame STOP codon upstream of the START methionine, and possessed, in the 3' UTR, an RNA instability motif, polyA+ consensus motifs and a polyA+ tail (Malter "Identification of an AUUUA-specific messenger RNA binding protein" Science 246:664-666, 1989). This cDNA appeared to encode a novel 179 amino acid open reading frame (FIG. 2). Structural analysis predicted a b-strand-rich, stable, soluble protein with a slightly acidic p1 (pH 5.4). No substantial regions of homology with any other sequence are present.

experiment iii

[0122] To determine the capacity of the isolated cDNA clone to produce resistance to Fas-mediated apoptosis, BAL-17 murine B lymphoma cells were transfected with the pBKCMV expression vector. BAL-17 cells were chosen because their activation responses mimic primary B cells in a variety of ways and they are readily transfectable (Chiles et al. "Cross-linking of surface Ig receptors on murine B lymphocytes stimulates the expression of nuclear tetradecanoyl phorbol acetate-response element binding-proteins" J. Immunol. 146:1730-1735, 1991; Mizuguchi et al. "Protein kinase C activation blocks anti-IgM-mediated signaling in BAL-17 B lymphoma cells" J. Immunol. 139:1054-1059, 1987; Seyfert et al. "Egr-1 expression in surface Ig-mediated B cell activation:kinetics and association with protein kinase C activation" J. Immunol. 145:3547-3553, 1990). Like primary B cells, unstimulated BAL-17 B cells express little Fas, but treatment with CD40L induces Fas expression and sensitivity to Fas-medi...

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Abstract

This invention generally relates to the nucleic acid sequences of a novel gene FAIM that encodes an apoptosis inhibiting protein. Furthermore, this invention relates to methods of identifying and testing antagonists of FAIM activity and screening for inter- and intra-specific homologs and mutants of FAIM.

Description

[0002] This invention generally relates to the nucleic acid sequences of a novel gene called the Fas Apoptosis Inhibitory Molecule (faim) that encodes an apoptosis inhibiting protein. Furthermore, this invention relates to methods of identifying and testing antagonists of FAIM activity and to methods to assay for FAIM expression.[0003] Programmed cell death (PCD) is mediated by a process called apoptosis. Although the investigation of cell death is a relatively new field of study, it has become readily apparent that many disease states are manifested due to the aberrant control of programmed cell death. Recent evidence suggest that the failure of cells to undergo apoptotic cell death might be involved in the pathogenesis of a variety of human diseases including cancer, autoimmune diseases and viral infections. The understanding of survival pathways would be critical in disease states where excessive cell numbers, such as in various cancers, are the result of cell death rather than c...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07K14/47
CPCC07K14/4747
Inventor ROTHSTEIN, THOMAS L.SCHNEIDER, THOMAS J.DONOHOE, TERRENCE J.
Owner BOSTON MEDICAL CENTER INC
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