ap20187 and Anemia

ap20187 has been researched along with Anemia* in 2 studies

Other Studies

2 other study(ies) available for ap20187 and Anemia

ArticleYear
In vivo regulation of erythropoiesis by chemically inducible dimerization of the erythropoietin receptor intracellular domain.
    PloS one, 2015, Volume: 10, Issue:3

    Erythropoietin (Epo) and its receptor (EpoR) are required for the regulation of erythropoiesis. Epo binds to the EpoR homodimer on the surface of erythroid progenitors and erythroblasts, and positions the intracellular domains of the homodimer to be in close proximity with each other. This conformational change is sufficient for the initiation of Epo-EpoR signal transduction. Here, we established a system of chemically regulated erythropoiesis in transgenic mice expressing a modified EpoR intracellular domain (amino acids 247-406) in which dimerization is induced using a specific compound (chemical inducer of dimerization, CID). Erythropoiesis is reversibly induced by oral administration of the CID to the transgenic mice. Because transgene expression is limited to hematopoietic cells by the Gata1 gene regulatory region, the effect of the CID is limited to erythropoiesis without adverse effects. Additionally, we show that the 160 amino acid sequence is the minimal essential domain of EpoR for intracellular signaling of chemically inducible erythropoiesis in vivo. We propose that the CID-dependent dimerization system combined with the EpoR intracellular domain and the Gata1 gene regulatory region generates a novel peroral strategy for the treatment of anemia.

    Topics: Amino Acid Sequence; Anemia; Animals; Erythropoiesis; Erythropoietin; GATA1 Transcription Factor; Gene Expression Regulation, Developmental; Mice; Mice, Transgenic; Protein Multimerization; Protein Structure, Tertiary; Receptors, Erythropoietin; Signal Transduction; Tacrolimus

2015
Death switch for gene therapy: application to erythropoietin transgene expression.
    Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas, 2010, Volume: 43, Issue:7

    The effectiveness of the caspase-9-based artificial "death switch" as a safety measure for gene therapy based on the erythropoietin (Epo) hormone was tested in vitro and in vivo using the chemical inducer of dimerization, AP20187. Plasmids encoding the dimeric murine Epo, the tetracycline-controlled transactivator and inducible caspase 9 (ptet-mEpoD, ptet-tTAk and pSH1/Sn-E-Fv'-Fvls-casp9-E, respectively) were used in this study. AP20187 induced apoptosis of iCasp9-modified C2C12 myoblasts. In vivo, two groups of male C57BI/6 mice, 8-12 weeks old, were injected intramuscularly with 5 microg/50 g ptet-mEpoD and 0.5 microg/50 g ptet-tTAk. There were 20 animals in group 1 and 36 animals in group 2. Animals from group 2 were also injected with the 6 microg/50 g iCasp9 plasmid. Seventy percent of the animals showed an increase in hematocrit of more than 65% for more than 15 weeks. AP20187 administration significantly reduced hematocrit and plasma Epo levels in 30% of the animals belonging to group 2. TUNEL-positive cells were detected in the muscle of at least 50% of the animals treated with AP20187. Doxycycline administration was efficient in controlling Epo secretion in both groups. We conclude that inducible caspase 9 did not interfere with gene transfer, gene expression or tetracycline control and may be used as a safety mechanism for gene therapy. However, more studies are necessary to improve the efficacy of this technique, for example, the use of lentivirus vector.

    Topics: Anemia; Animals; Caspase 9; Dimerization; Erythropoietin; Gene Expression; Genetic Therapy; Genetic Vectors; Hematocrit; Injections, Intramuscular; Lentivirus; Male; Mice; Mice, Inbred C57BL; Plasmids; Recombinant Proteins; Tacrolimus

2010