Life Sciences Commons^™

In Vitro Functional Analysis Of Novel Single Nucleotide Polymorphisms In Oatp1b1 And Potential Clinical Relevance, Zhiyuan P. Yin

Electronic Thesis and Dissertation Repository

Statin-induced myopathy is a common adverse reaction of statin therapy. Patients with elevated plasma concentration of statins are thought to be at greater risk for myopathy. Statins are transported from the blood to hepatocytes via organic anion transporting polypeptide 1B1 (OATP1B1). Although single nucleotide polymorphisms (SNPs) in OATP1B1 have been associated with increased statin concentrations, we hypothesize that there may be other SNPs in OATP1B1 that can also contribute to reduced transport activity and increased plasma statin concentrations. OATP1B1 cDNA packaged in pEF6/V5-His TOPO was used as template, and 6 SNPs — c.298G>A, c.419C>T, c.463C>A (*4), c.1007C …

Analysis Of The Vascular Phenotype Of The Ent1-Null Mouse, Keisha A. Best

Electronic Thesis and Dissertation Repository

Adenosine is important in the regulation of vascular tone and the Equilibrative Nucleoside Transporter 1 (ENT1) is a regulator of adenosine concentrations. Thus, changes in ENT1 expression and activity may alter vascular tone regulation. We therefore examined the cardiovascular phenotype of ENT1-null (ENT1^-/-) as compared to wild type mice (ENT1^+/+). Heart rates (HRs) and blood pressures (BPs) of ENT1^-/- and ENT1^+/+ littermate male mice were obtained while conscious and anaesthetized, and metabolic data were collected over a 24 hr period. Vascular reactivity was assessed in aortic ring segments obtained from 3 month old ENT1 …

Erythropoietin And Chronic Kidney Disease Alter Hepatic Expression Of Cytochrome P450 Enzymes And Drug Transport Proteins, David A. Feere

Electronic Thesis and Dissertation Repository

Chronic kidney disease (CKD) is a progressive disease involving the irreversible loss of kidney function. Patients with CKD require concurrent dosing of many medications to manage their disease and associated comorbidities. Pharmacokinetic studies using patients with CKD and previous studies using animal models of CKD have demonstrated changes in hepatic drug metabolism and transport. Our studies aim to examine the effects that end-stage renal disease (ESRD) and continuous dosing of recombinant human erythropoietin (EPO) have on hepatic cytochrome P450 (P450) drug metabolizing enzymes and drug transport proteins. We used an adenine-fed rat model of CKD to demonstrate that EPO decreases …

Effect Of Ascorbate On Coagulation And Fibrinolytic Factors In The Septic Microvasculature, Scott Swarbreck

Electronic Thesis and Dissertation Repository

Sepsis, a systemic inflammatory response to an infection, is a significant cause of morbidity and mortality worldwide. The microcirculation during sepsis fails, in part, due to microthrombosis and the resulting plugging of capillaries, precipitating organ failure. Intravenous injection of ascorbate has been shown to reduce capillary plugging, however the mechanism of this protective effect is unclear. We hypothesized that ascorbate-mediated destabilization of the microthrombi through promoting fibrinolysis could contribute to this protection.

We showed that streptokinase, a pro-fibrinolytic agent, reduced the capillary plugging to a similar degree as ascorbate. This similarity provided the impetus for studying the effect of ascorbate …

Sirna Targeting Of Thymidylate Synthase, Thymidine Kinase 1 And Thymidine Kinase 2 As An Anticancer Therapy: A Combinatorial Rnai Approach, Christine Di Cresce

Electronic Thesis and Dissertation Repository

Thymidylate synthase (TS) is the only de novo source of thymidylate (dTMP) for DNA synthesis and repair. Drugs targeting TS protein are a mainstay in cancer treatment but off-target effects and toxicity limit their use. Cytosolic thymidine kinase (TK1) and mitochondrial thymidine kinase (TK2) contribute to an alternative dTMP-producing pathway, by salvaging thymidine from the tumour milieu, and may modulate resistance to TS-targeting drugs. We have previously shown that TS antisense molecules (oligodeoxynucleotides, ODNs, and small interfering siRNA, siRNA) sensitize tumour cells, both in vitro and in vivo, to TS targeting drugs. As both TS and TKs contribute to cellular …