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- 저자 : Hesselson, Stephanie (검색결과 2 건)
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Ha Choi, Ji,Wah Yee, Sook,Kim, Mee J.,Nguyen, Loan,Ho Lee, Jeong,Kang, Ji-One,Hesselson, Stephanie,Castro, Richard A.,Stryke, Doug,Johns, Susan J.,Kwok, Pui-Yan,Ferrin, Thomas E.,Goo Lee, Min,Black, B Lippincott Williams Wilkins, Inc. 2009 Pharmacogenetics and genomics Vol.19 No.10
OBJECTIVES: Human multidrug and toxin extrusion member 1, MATE1 (SLC47A1), plays an important role in the renal and biliary excretion of endogenous and exogenous organic cations including many therapeutic drugs. In this study, we characterized the transcriptional effects of five polymorphic variants and six common haplotypes in the basal promoter region of MATE1 that were identified in 272 DNA samples from ethnically diverse US populations. METHODS: We measured luciferase activities of the six common promoter haplotypes of MATE1 using in-vitro and in-vivo reporter assays. RESULTS: Haplotypes that contain the most common variant (mean allele frequency in four ethnic groups: 0.322), g.–66T>C, showed a significant decrease in reporter activities compared to the reference. Two transcription factors, activating protein-1 (AP-1) and activating protein-2 repressor (AP-2rep), were predicted to bind to the promoter in the region of g.–66T>C. Results from electrophoretic mobility shift assays showed that the g.–66T allele, exhibited greater binding to AP-1 than the g.–66C allele. AP-2rep inhibited the binding of AP-1 to the MATE1 basal promoter region, and the effect was considerably greater for the g.–66T>C. These data suggest that the reduced transcriptional activity of g.–66T>C results from a reduction in the binding potency of the transcriptional activator, AP-1, and an enhanced binding potency of the repressor, AP-2rep to the MATE1 basal promoter region. Consistent with the reporter assays, MATE1 mRNA expression levels were significantly lower in kidney samples from individuals who were homozygous or heterozygous for g.–66T>C in comparison with samples from individuals who were homozygous for the g.–66T allele. CONCLUSION: Our study suggests that the rate of transcription of MATE1 is regulated by AP-1 and AP-2rep and that a common promoter variant, g.–66T>C may affect the expression level of MATE1 in human kidney, and ultimately result in variation in drug disposition and response.
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Advanced pathophysiology mimicking lung models for accelerated drug discovery
Thanh Huyen Phan,Huaikai Shi,Christopher E. Denes,Alexander J. Cole,Yiwei Wang,Yuen Yee Cheng,Daniel Hesselson,Susan H. Roelofs,Graham Gregory Neely,Jun‑Hyeog Jang,Wojciech Chrzanowski 한국생체재료학회 2023 생체재료학회지 Vol.27 No.00
Background Respiratory diseases are the 2nd leading cause of death globally. The current treatments for chronic lung diseases are only supportive. Very few new classes of therapeutics have been introduced for lung diseases in the last 40 years, due to the lack of reliable lung models that enable rapid, cost-effective, and high-throughput testing. To accelerate the development of new therapeutics for lung diseases, we established two classes of lung-mimicking models: (i) healthy, and (ii) diseased lungs – COPD. Methods To establish models that mimic the lung complexity to different extents, we used five design components: (i) cell type, (ii) membrane structure/constitution, (iii) environmental conditions, (iv) cellular arrangement, (v) substrate, matrix structure and composition. To determine whether the lung models are reproducible and reliable, we developed a quality control (QC) strategy, which integrated the real-time and end-point quantitative and qualitative measurements of cellular barrier function, permeability, tight junctions, tissue structure, tissue composition, and cytokine secretion. Results The healthy model is characterised by (i) continuous tight junctions, (ii) physiological cellular barrier function, (iii) a full thickness epithelium composed of multiple cell layers, and (iv) the presence of ciliated cells and goblet cells. Meanwhile, the disease model emulates human COPD disease: (i) dysfunctional cellular barrier function, (ii) depletion of ciliated cells, and (ii) overproduction of goblet cells. The models developed here have multiple competitive advantages when compared with existing in vitro lung models: (i) the macroscale enables multimodal and correlative characterisation of the same model system, (ii) the use of cells derived from patients that enables the creation of individual models for each patient for personalised medicine, (iii) the use of an extracellular matrix proteins interface, which promotes physiological cell adhesion and differentiation, (iv) media microcirculation that mimics the dynamic conditions in human lungs. Conclusion Our model can be utilised to test safety, efficacy, and superiority of new therapeutics as well as to test toxicity and injury induced by inhaled pollution or pathogens. It is envisaged that these models can also be used to test the protective function of new therapeutics for high-risk patients or workers exposed to occupational hazards.
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