dc.contributor.author | Peterson, Kenneth R. | |
dc.contributor.author | Costa, Flávia C. | |
dc.contributor.author | Fedosyuk, Halyna | |
dc.contributor.author | Neades, Renee Y. | |
dc.contributor.author | Chazelle, Allen M. | |
dc.contributor.author | Zelenchuk, Lesya | |
dc.contributor.author | Fonteles, Andrea H. | |
dc.contributor.author | Dalal, Parmita | |
dc.contributor.author | Roy, Anuradha | |
dc.contributor.author | Chaguturu, Rathnam | |
dc.contributor.author | Li, Biaoru | |
dc.contributor.author | Pace, Betty S. | |
dc.date.accessioned | 2014-11-04T17:37:34Z | |
dc.date.available | 2014-11-04T17:37:34Z | |
dc.date.issued | 2014-09-16 | |
dc.identifier.citation | Peterson KR, Costa FC, Fedosyuk H, Neades RY, Chazelle AM, et al. (2014) "A Cell-Based High-Throughput Screen for Novel Chemical Inducers of Fetal Hemoglobin for Treatment of Hemoglobinopathies." PLoS ONE 9(9): e107006. http://dx.doi.org/10.1371/journal.pone.0107006 | |
dc.identifier.uri | http://hdl.handle.net/1808/15538 | |
dc.description | This is the published version, also available here, http//dx.doi.org/10.1371/journal.pone.0107006. | |
dc.description.abstract | Decades of research have established that the most effective treatment for sickle cell disease (SCD) is increased fetal
hemoglobin (HbF). Identification of a drug specific for inducing c-globin expression in pediatric and adult patients, with
minimal off-target effects, continues to be an elusive goal. One hurdle has been an assay amenable to a high-throughput
screen (HTS) of chemicals that displays a robust c-globin off-on switch to identify potential lead compounds. Assay systems developed in our labs to understand the mechanisms underlying the c- to b-globin gene expression switch during
development has allowed us to generate a cell-based assay that was adapted for a HTS of 121,035 compounds. Using
chemical inducer of dimerization (CID)-dependent bone marrow cells (BMCs) derived from human c-globin promoter-firefly
luciferase b-globin promoter-Renilla luciferase b-globin yeast artificial chromosome (c-luc b-luc b-YAC) transgenic mice, we were able to identify 232 lead chemical compounds that induced c-globin 2-fold or higher, with minimal or no b-globin
induction, minimal cytotoxicity and that did not directly influence the luciferase enzyme. Secondary assays in CIDdependentwild-type b-YAC BMCs and human primary erythroid progenitor cells confirmed the induction profiles of sevenof the 232 hits that were cherry-picked for further analysis. | |
dc.description.sponsorship | This work was supported by Public Health Service National Institutes of Health (NIH.gov) grants HL069234 to BSP (subcontract to KRP), and HL067336, DK061804, and DK081290 to KRP. KU-HTSL is a KU Cancer Center Shared Resource, and is funded in part by National Intitutes of Health COBRE Grant 8 P30 GM103495 (B. Timmermann, PI) and the NCI Cancer Support Grant, 5 P30 CA168524 (R. Jensen, PI). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. | |
dc.publisher | Public Library of Science | |
dc.title | A Cell-Based High-Throughput Screen for Novel Chemical Inducers of Fetal Hemoglobin for Treatment of Hemoglobinopathies | |
dc.type | Article | |
kusw.kuauthor | Roy, Anuradha | |
kusw.kuauthor | Chaguturu, Rathnam | |
kusw.kudepartment | High Throughput Screening Laboratory | |
kusw.oastatus | fullparticipation | |
dc.identifier.doi | 10.1371/journal.pone.0107006 | |
dc.identifier.orcid | https://orcid.org/0000-0001-9990-3303 | |
kusw.oaversion | Scholarly/refereed, publisher version | |
kusw.oapolicy | This item meets KU Open Access policy criteria. | |
dc.rights.accessrights | openAccess | |