Browsing by Author "Rouse, Evan"

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    Drug Discovery Through Drug Perturbation Pathway Modeling and Network Analysis
    (Office of the Vice Chancellor for Research, 2014-04-11) Ho, Tung; Hakola, Krista; Wagle, Pragat; Rouse, Evan; Shadmand, Mehdi; Han, Juyeon; Ibrahim, Sara
    Due to intrinsic complex molecular interactions, the “one disease – one target – one drug” strategy for disease treatment is no longer the best option to treat cancers. To assess drug pharmacological effects, we assume that “ideal” drugs for a patient can treat or prevent the disease by modulating gene expression profiles of this patient to the similar level with those in healthy people. A new approach for drug-protein interactions curation, drug-drug similarity network comparison, and integrative pathway model construction and evaluation was introduced to determine optimal drugs for various cancers. Drug-protein interaction curation is conducted to discover novel drug-protein relationships and is categorized as: up regulated, down regulated, indirect up or down, ambiguous and unknown. The manual curation can be utilized for drug repurposing and examining drug mechanism on a pathway level. A drug-drug similarity network model is built by examining similar targets, therapeutic mechanisms, side effects, and chemical structures. Drug similarity analysis is useful for drug repositioning because similar drugs may have compatible therapeutic or toxic effects for a disease. Drug similarity networks are constructed and examined through a molecular network visualization platform. An integrative disease-specific pathway model is also built to gain a more holistic view of disease mechanisms by including every significant disease-specific protein. Including drugs on the pathway through target information can also offer a clear mechanism for the drug’s action. We also transform integrated pathways into network models and ranked drugs based on the network topological features of drug targets, drug-affecting genes/proteins, and curated disease-specific proteins. Combining our three approaches could potentially lead to advances in drug repurposing and repositioning.
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    Phenylephrine, a common cold remedy active ingredient, suppresses uterine contractions through cAMP signalling
    (Springer Nature, 2018-08-03) Chen, Xingjuan; Meroueh, Marya; Mazur, Gabriela; Rouse, Evan; Hundal, Karmjot Singh; Stamatkin, Christopher W.; Obukhov, Alexander G.; Cellular and Integrative Physiology, School of Medicine
    Regulation of uterine contractility is an important aspect of women's health. Phenylephrine, a selective agonist of the α1-adrenoceptor and a potent smooth muscle constrictor, is widely used in women even during pregnancy to relieve cold-related symptoms, to treat postpartum haemorrhoid, and during routine eye exams. We performed isometric tension recordings to investigate the effect of phenylephrine on mouse uterine contractility. Phenylephrine decreased spontaneous and oxytocin-induced contractions in non-pregnant mouse uterine rings and strips with an IC50 of ~1 μM. Prazosin, an inhibitor of α1-adrenoceptor, did not prevent phenylephrine-mediated relaxations. Conversely, ICI118551, an antagonist of β2-adrenoceptors, inhibited phenylephrine relaxation. In the presence of ICI118551, high concentrations (>30 μM) of phenylephrine caused mouse uterine contractions, suggesting that β-adrenoceptor-mediated inhibition interferes with the phenylephrine contractile potential. Phenylephrine-dependent relaxation was reduced in the uterus of pregnant mice. We used primary mouse and human uterine smooth muscle cells (M/HUSMC) to establish the underlying mechanisms. Phenylephrine stimulated large increases in intracellular cAMP in M/HUSMCs. These cAMP transients were decreased when HUSMCs were cultured in the presence of oestrogen and progesterone to mimic the pregnancy milieu. Thus, phenylephrine is a strong relaxant in the non-pregnant mouse uterus, but exhibits diminished effect in the pregnant uterus.