Medical Pharmacology and Physiology electronic theses and dissertations (MU)
Permanent URI for this collection
The items in this collection are the theses and dissertations written by students of the Department Medical Pharmacology and Physiology. Some items may be viewed only by members of the University of Missouri System and/or University of Missouri-Columbia. Click on one of the browse buttons above for a complete listing of the works.
Browse
Recent Submissions
Item Potential therapeutic target for DMD-associated cardiomyopathy : SHP2(University of Missouri--Columbia, 2025) Chynoweth, Bryn; Krenz, MaikeDuchenne Muscular Dystrophy (DMD) is a severe degenerative muscle disorder caused by deletion, duplication, or point mutation in the gene encoding dystrophin. As advancements in respiratory support have increased DMD patient lifespan, dilated cardiomyopathy has become a concerning source of morbidity and mortality in DMD, underscoring the need for further research in this area. Pilot data from our lab has shown that Src homology region 2 domain-containing phosphatase-2 (SHP2) inhibition may have cardioprotective effects. SHP2 is a protein tyrosine phosphatase that dephosphorylates proteins involved in several cellular processes. We investigated the potential beneficial effects of SHP2 inhibition through analysis of cardiac muscle function and histology in DMD mice. To genetically reduce SHP2 activity, we generated mice that express dominant negative SHP2 (dnSHP2) in cardiac myocytes. For this project, dnSHP2 mice were crossed with Dmdmdx-4Cv (referred to throughout as mdx) mice to determine the extent of the hypothesized protective effects. To quantify fibrosis, hearts from 18+ months old mice were fixed with 4% paraformaldehyde in cardioplegic buffer and sections stained with Gomori trichrome. To compare ejection fraction, fractional shortening, and chamber dimensions between control (wildtype with/without dnSHP2) and experimental groups (mdx with/without dnSHP2), anesthetized 4--7-month-old mice underwent high-resolution echocardiography. After acclimatization, conscious echocardiography was performed on mice aged 22-24 months. Data collected show a significant reduction in left ventricular fibrosis in dnSHP2; mdx/y mice. Additionally, dnSHP2; mdx/y mice exhibit marked improvements in ejection fraction and fractional shortening compared to non-transgenic (NTG) mdx/y mice. These improvements were particularly pronounced in the aged cohort. The cardioprotective effects observed support additional investigation into SHP2 as a possible therapeutic target.Item Effect of a novel contraceptive compound on vaginal health(University of Missouri--Columbia, 2024) Carulli, Erin M.; Winuthayanon, WipaweeIn 2011, 49 percent of pregnancies in the United States were unintended. There are currently available over the counter contraceptive options, such as condoms and spermicides, but these methods have failure rates between 13-21 percent. Additionally, spermicides can cause damage to the vaginal epithelium and can increase susceptibility to sexually transmitted diseases (STDs). As such, our laboratory has identified a novel non-hormonal contraceptive method to block the semen liquefaction process using a small molecule inhibitor called triazole B1. B1 acts to block the activity of prostate specific antigen, the serine protease responsible for initiating the liquefaction process by cleaving the protein SEMG-1. B1 is intended to be used as a local vaginal gel contraceptive and not as a systemic drug. Therefore, we need to address whether B1 can penetrate the vaginal epithelial layer. Using human liver microsomes (HLM), we found that B1 is not fully metabolized by liver microsomes and is detectable by UHPLC- MS in its original form. To determine if B1 can traverse the vaginal epithelium and enter circulation, we preformed tissue permeation experiments using Mattek's 3D human EpiVaginal tissue. B1 was not able to traverse human vaginal ectocervical cells in vitro. Next, we tested B1's permeability in a murine in vivo model, again finding that B1 was not able to permeate the vaginal epithelial layer. Together, these findings suggest that B1 will remain within the vagina and not reach systemic circulation.Item Comparing calcium handling in right and left ventricle cardiomyocytes in type III pulmonary hypertension(University of Missouri--Columbia, 2024) Shahid, Arooj; Domeier, Timothy L.Type III pulmonary hypertension (PH) is characterized by pulmonary fibrosis, leading to elevated pressure in the pulmonary arteries and hypertrophy of the right ventricle (RV). Yet, effects of PH on cardiomyocyte calcium handling are unclear. This study addresses the hypothesis that RV cardiomyocytes will show altered excitation-contraction coupling (ECC) as compared to left ventricle (LV) cardiomyocytes in a mouse PH model. To assess this, male C57BL/6 mice were treated with intratracheal saline (sham) or bleomycin (Bleo;0.025 units) to induce type III PH. On days 21-24 post-treatment, animals were anesthetized, hearts were excised, and perfused for enzymatic cell isolation. Isolated RV and LV cardiomyocytes were loaded with fluo-5F for calcium measurements during ECC. Calcium transient amplitude was measured at 0.5 Hz, and sarcoplasmic reticulum (SR) calcium content was determined by rapid application of 10 mM caffeine. Bleo-treated mouse hearts showed RV hypertrophy, indicating PH development and RV remodeling. Calcium transient amplitude and reuptake kinetics reveal ECC alterations and impaired SR Calcium ATPase (SERCA) activity in RV cardiomyocytes of the PH model. Interestingly, SR calcium content was not different between Bleo and sham groups in either RV or LV cardiomyocytes. Thus, this study emphasizes mechanisms underlying RV versus LV dysfunction in type III PH, indicating therapeutic interventions targeting cardiomyocyte calcium handling may improve outcomes in patients with PH.Item Female sex protects cerebral arteries from mitochondrial membrane potential depolarization and cell death induced by reactive oxygen species(University of Missouri--Columbia, 2024) Safa; Norton, Charles E.Stroke, Alzheimer's disease, and traumatic brain injury exacerbate the production of reactive oxygen species (ROS), leading to apoptosis in cerebral arteries. Notably, females exhibit greater resilience to vascular damage compared to males. Mitochondrial membrane potential ([delta][psi]m) depolarization is a pivotal event in apoptosis. However, under significant depolarization, ATP synthase can reverse direction, acting as a proton pump to mitigate [delta][psi]m depolarization. Additionally, alterations in the electron transport chain function may regulate [delta][psi]m. Furthermore, plasminogen activator inhibitor-1 (PAI-1), a serine protease inhibitor present in cerebral arteries, can promote cellular resilience, although its effects on mitochondrial function have not been defined. We hypothesize that during acute oxidative stress induced by exposure to H2O2, female protection of posterior cerebral arteries (PCAs) is facilitated by enhanced reverse ATP synthase activity, augmented mitochondrial electron transport function, and PAI-1 signaling. PCAs (80 [mu]m diameter) from male and female mice (age: 4-6 months) were isolated, cannulated, and pressurized to 90 cm H2O2 at 37 degreesC. Cell death was quantified with Hoechst 33342 (1 [mu]M, labels all nuclei) and propidium iodide (2 [mu]M, labels dead nuclei), and mitochondrial membrane potential ([delta][psi]m) at rest was evaluated by JC-1 and during depolarization with H2O2 with tetramethylrhodamine methyl ester (TMRM, 10 nM). H2O2 exposure (50 min) led to significantly (P<0.05) greater smooth muscle cell death in males compared to females (30 [plus or minus] 7.4 percent vs. [approx] 7 [plus or minus] 3 percent; n=8); there was a similar trend for endothelial cell death. The ATP synthase inhibitor oligomycin (2 [mu]M) greatly augmented apoptosis in PCAs from both males and females to [approx]80 percent and eliminated differences between sexes. Consistently, H2O2 evoked a more robust depolarization of [delta][psi]m in males vs. females and oligomycin enhanced [delta][psi]m depolarization to H2O2. Oxygen consumption rate (OCR) in females was significantly higher at baseline and when exposed to H2O2, while glycolysis was not altered by exposure to H2O2. In females, PAI-1 signaling contributes to resilience against acute oxidative stress damage, whereas males exhibit greater protection in the absence of PAI-1. We conclude that cerebral vessels from female mice possess greater resilience to H2O2 -induced apoptosis than males by limiting depolarization of [delta][psi]m and though sex differences in PAI-1 signaling.Item The impact of cadmium and nickel on non-small cell lung cancer progression in vitro analysis of tumor progression(University of Missouri--Columbia, 2024) Otoboh, Mary Omonyokan; Parish, AlanLung cancer ranks among the primary contributors to cancer-related fatalities globally, affecting both men and women (Zhai et al., 2019). Lung cancer begins when healthy cells in the lungs undergo genetic mutations that disrupt their normal growth and death cycle (Fong et al., 2008). These mutated cells divide uncontrollably, forming tumors and disrupting lung function. In 2015, lung cancer diagnoses affected 221,200 individuals in the United States, and this disease claimed the lives of another 158,040 individuals (Townsend et al., 2017). Annually, approximately 230,000 individuals in the United States receive a diagnosis of lung cancer, leading to an estimated 135,000 deaths per year. The mortality rate linked to lung cancer now surpasses the combined fatalities from prostate, breast, brain, and colorectal cancer.