Pharmacology Commons^™

Heat Shock Factor 1 Signaling: A Novel Pathway Implicated In Rett Syndrome Pathophysiology, Sonia Gonzalez

Dissertations

Rett syndrome (RTT) is a severe neurodevelopmental disorder that is associated with loss-of-function mutations in the methyl-CPG binding protein 2 (MECP2) gene. There are limited therapeutic options to address the wide range of social, cognitive, motor, and respiratory symptoms that patients experience throughout their lifetime. To identify novel therapeutic targets, we leveraged a rare form of RTT known as MeCP2-mutation-negative or atypical RTT. Traditionally, RTT is first diagnosed clinically and then confirmed through the identification of mutations in the MECP2 gene. However, ~5% of RTT patients are found to be MeCP2-mutation-negative (atypical), despite sharing overlapping symptomology with typical RTT. We …

Muscarinic Acetylcholine Receptor 1: Implications For Precision Medicine And Rett Syndrome Therapeutics, Mackenzie Smith

Dissertations

Rett syndrome (RTT) is a rare neurodevelopmental disorder caused by mutations in the gene coding for methyl-CpG binding protein 2 (MeCP2). Currently, there is no cure for RTT and few effective treatment options to address the social, cognitive, motor, and respiratory symptoms that patients face. With the goal of identifying novel targets, our lab performed RNA-sequencing experiments in human autopsy samples and found decreased levels of the M1 muscarinic acetylcholine receptor. We have established that potentiation of this receptor in a Mecp2+/- mouse model of RTT rescues social, cognitive, and respiratory phenotypes, providing support for using drugs that act on …

Investigating Whether Txnrd2 Is A Therapeutic Target Against Triple Negative Breast Cancer Using African American-Derived Models, Keacha Chang

Dissertations

Despite similar breast cancer incidence rates, African American (AA) women experience a 40% higher mortality rate compared to Caucasian American (CA) women. This disparity is multifactorial and particularly pronounced in the Chicago area. AA women are twice as likely to be diagnosed with triple-negative breast cancer (TNBC), often at a younger age and with more aggressive disease. TNBC is a heterogeneous subtype lacking targeted therapies and is associated with the poorest prognosis among breast cancer types. Therefore, there is an urgent need for novel therapeutic strategies for TNBC, especially those tailored to AA patients. The thioredoxin pathway is essential for …

Tak1 Blockade Plus Azacitidine Induces Apoptosis, Augments Cytarabine, And Ablates Clonogenicity In Mll-Af9+ Human Aml Cell Lines, Austin P. Runde, Cameron Lewis, Peter Breslin Sj, Jiwang Zhang

School of Medicine

Acute myeloid leukemia (AML) encompasses a diverse group of cancers that originate in the blood-forming tissues of the bone marrow [1]. Aside from the PML-RARA⁺ subtype, AML carries a 5-year survival rate of 28% for patients 20+ years of age. AML is the most common cancer of the hematopoietic system and is slightly more common in biological males; the average age at diagnosis is 68 years. Standard frontline treatment for AML is a two-phase regimen of intensive chemotherapy (CTx) employing daunorubicin and cytarabine; etoposide may also be added in select regimens. Despite 60-70% of patients achieving complete remission (CR), …

Development Of Targeted, Statin Loaded Nanoparticle Delivery Systems, Stephanie Judkins

Master's Theses

Statins lower endogenous production of cholesterol through their inhibition of the mevalonate pathway. Lipophilic statins in particular exhibit anti-inflammatory effects at supraphysiological doses by preventing downstream signaling through small molecule GTPases. Interest lies in development of statins as anti-inflammatory therapeutics, however, achieving effective doses locally incurs serious off-target effects. Our goal was to develop and optimize a targeted delivery system to traffic these drugs to inflamed sites and unload the drug at effective concentrations while avoiding systemic exposure. Lipophilic statins (lovastatin, simvastatin, and atorvastatin) were incorporated into polymeric nanoparticles (NPs) due to their hydrophobicity. We have shown that statins released …

The Role Of Extracellular Vesicles And Their Cargo In Intercellular Communication, Chongyu Zhang

Dissertations

Extracellular vesicles (EVs) are membranous vesicles secreted by most cells. They contain lipids, proteins, and nucleic acids, including microRNAs (miRNA), and function in intercellular communication by endocytosis into other cells. EVs in diseased states carry miRNAs and proteins reflective of the changed state of cells and can be endocytosed into other cells to exert regulatory effects. Thus, EVs represent a form of paracrine genetic regulation in health and disease. Myocardial infarction (MI) and pulmonary embolism (PE) are leading causes of cardiovascular deaths worldwide. It is important to develop new diagnostic and therapeutic approaches that could lead to medical advances. Circulating …

Comparative Studies On Biochemical And Pharmacological Profiles Of Unfractionated Heparins & Their Depolymerized Derivatives From Bovine, Ovine And Porcine Origins, Ahmed Kouta

Dissertations

Heparin and heparin related drugs have remained the anticoagulant of choice for medical and surgical indications. These drugs are comprised of poly-component sulfated chains of varying length and biophysical structure with direct and indirect pharmacological effects. Heparins produce their therapeutic effects by multiple mechanisms involving both the cellular and humoral targets. These drugs represent natural products which are isolated from mammalian tissue rich in mast cells. Currently used heparin and LMWHs are obtained from porcine mucosal tissue. Other animal sources including bovine and ovine tissues also provide additional sources for the manufacturing of heparins. While there may be microchemical and …

Reducing Reperfusion Injury In An Adult Rat Stroke Model With St-115 Treatment, Morgan Rae Lenz

Master's Theses

The restoration of blood flow to ischemic cerebral tissue can result in reperfusion injury, and blocking reperfusion injury can significantly aid in recovery of ischemic tissue. Bradykinin has been shown to exhibit protective effects, but does not reach protective levels during reperfusion due to inactivation by aminopeptidase P2 (APP2). Therefore, inhibiting APP2 during reperfusion is a potential therapeutic strategy to aid in the reduction of reperfusion injury, leading to the development of ST-115, an APP2 inhibitor. It was hypothesized that administration of ST-115 during ischemic stroke, and just prior to reperfusion, will result in reduced neurological injury and increased functional …

Elucidation Of The Molecular Mechanisms Of Electrically-Induced Cardioprotection, Anne Elizabeth Roessler

Dissertations

Cardiovascular disease is the leading cause of death worldwide. A myocardial infarction (MI), commonly known as a heart attack, is a major event in cardiovascular disease characterized by reduced blood flow to the heart. The ischemia and reperfusion (I/R) injury associated with an MI results in a region of dead tissue in the heart called an infarct, the size of which influences patient prognosis. In the 1980s, it was discovered that short, non-lethal episodes of I/R, termed ischemic preconditioning (IPC), can protect the heart against a subsequent MI. Ischemic preconditioning demonstrated the phenomenon of endogenous cardioprotection. Cardioprotection has great potential …

Examining The Regulation Of Kv7 K+ Channels In Airway Smooth Muscle Cells And Their Potential As Novel Therapeutic Targets For The Treatment Of Asthma, Jennifer Haick

Dissertations

Asthma is a disease characterized by nonspecific and exaggerated airway narrowing, termed airway hyperresponsiveness (AHR), which involves the excessive contraction of airway smooth muscle. Despite the fact that airway smooth muscle is widely studied and understood to play a role in AHR, little is known about the specifics of that role. Our laboratory recently found that Kv7 potassium (K+) channels are expressed in airway smooth muscle cells (ASMCs). Kv7 channels are voltage sensitive K+ channels whose outward flux of K+ ions promotes a negative resting membrane voltage in excitable cells, thereby opposing electrical excitability. Inhibition of K+ channels is known …

Phosphodiesterase Inhibition As A Mechanism Of Ion Channel Modulation By Celecoxib, Christina Jean Robakowski

Master's Theses

The overall objective of this thesis work is to determine the mechanism by which celecoxib modulates Kv7 potassium channels in vascular smooth muscle cells. The central hypothesis of the project is that celecoxib modulates Kv7 potassium channels in vascular smooth muscle cells through inhibition of phosphodiesterase 4 (PDE4, which catalyzes the breakdown of cyclic adenosine monophosphate (cAMP)), thereby activating a cAMP/protein kinase A (PKA) signaling pathway. The aims of this thesis targeted different points in the cAMP/PKA pathway with pharmacological interventions using whole cell perforated patch clamp electrophysiology and biochemical methods.

The data suggest multiple mechanisms by which celecoxib could …

Vascular Kv7 (Kcnq) Potassium Channels As Therapeutic Targets In Cerebral Vasospasm, Bharath Kumar Mani

Dissertations (6 month embargo)

Cerebral vasospasm, a grave sequel to subarachnoid hemorrhage (SAH), is characterized by prolonged severe constriction of arteries in the base of the brain, including the basilar artery. Spasmogens (serotonin, endothelin and vasopressin), elevated in response to SAH, induce persistent depolarization of the myocytes in the artery wall, leading to continuous influx of calcium (Ca2+) through voltage-sensitive Ca2+ channels (VSCC) resulting in hyperconstriction (spasm). The spasm of the arteries restricts blood flow to the brain, inducing ischemic neurological deficits and consequential high morbidity and mortality. The cellular pathogenesis of cerebral vasospasm is poorly understood and the therapeutic options are limited.

Kv7 …

Kv7 K+ Channels In Airway Smooth Muscle Cells As Target For Asthma Therapy, Priyanka Prakash Kakad

Master's Theses

Airway hyperresponsiveness (AHR) is an important etiological feature of asthma, the molecular mechanisms of which are poorly understood, thus preventing development of specific and effective therapies. We investigate the role played by Kv7 voltage-activated potassium channels in the pathophysiology of AHR and evaluate the significance of their regulation in treatment of asthma. Our studies provide the first evidence for expression of multiple Kv7 channels in guinea pig and human airways and demonstrate that the expression of Kv7 channels is reduced in allergen-sensitized guinea pig airways. Our ex vivo functional studies reveal that clinically available Kv7 channel activators attenuate the bronchoconstrictor …

Compositional Determinants Of The Pharmacological Actions Of Heparins, Angel Lee Gray-Shah

Dissertations

This dissertation primarily focuses on how differences in molecular weight (MW) and structural composition affect the pharmacological activity of heparin and its derivatives. Heparins are a mixture of glycosaminoglycans chains which are used to prevent thrombosis in a number of clinical indications. Heparins promote the inhibition of blood coagulation via their plasmatic cofactors antithrombin (AT) and heparin cofactor II (HCII).

In these studies, various heparins with molecular weights ranging from 2.6 to 16.5 kDa were investigated. Not only the molecular weight but also the oligosaccharide composition greatly varied in these agents. One of the major objectives of this research was …

Gabab Regulation Of Methamphetamine-Induced Associative Learning, Robin Michelle Voigt

Dissertations

Addiction is a chronic, relapsing disorder for which strikingly few effective therapies exist, and there are no FDA-approved pharmacotherapies for methamphetamine (Meth) addition. There is an immense need to identify the neurobiological underpinnings of psychostimulant addiction and develop efficacious drug therapies to compliment the current mainstay treatment of behavioral/cognitive therapy.

Re-exposure to cues associated with psychostimulants (e.g., drug paraphernalia) increase neuronal activity and can elicit drug-craving and -seeking; an effect which is profound and long-lasting. A mechanism to disrupt those brain processes which are necessary to maintain the association may reduce the incidence of cue-elicited relapse.

Conditioned place preference (CPP) …

Corticosteroid Modulation Of Hippocampal Neural Activity, Dayne Y. Okuhara

Dissertations

No abstract provided.

Effect Of Af64a On Rat Brain Septo-Hippocampal And Striatal Cholinergic Systems: A Neurochemical And Molecular Analysis, Qing Ivy Fan

Dissertations

No abstract provided.

Amyloid-β Deposition In Rat Brain: Histopathological And Functional Sequelae, Einar M. Sigurdsson

Dissertations

No abstract provided.

Characterization Of Adaptive Changes In 5-Htia Receptor Systems Induced By Repeated Injections Of 5-Ht Uptake Inhibitors, Qian Li

Dissertations

No abstract provided.

Androgen Receptors In The Hippocampus: Localization, Autoregulation, And Modulation Of Gene Expression In The Adult Male Rat, Janice E. Kerr

Dissertations

No abstract provided.

Characterization Of Central Serotonergic Alterations In Male Rats Following Prenatal Exposure To Fluoxetine, Theresa M. Cabrera

Dissertations

No abstract provided.

Comparative Pharmacologic Studies On Synthetic And Recombinant Inhibitors Of Thrombin, Demetra D. Callas

Dissertations

No abstract provided.

Relationships Between The Expression Of Genes Involved In The Regulation Of Apoptosis And Cell Death Induced By Nitrogen Mustard In Human Colon Carcinoma Cell Lines, Greggory Bernard Herbert

Dissertations

No abstract provided.

Pharmacologic Studies On Synthetic Analogues Of Heparin With Selective Affinity To Endogenous Serine Protease Inhibitors, Walter P. Jeske

Dissertations

No abstract provided.

Dopaminergic Modulation Of Basal Forebrain Cholinergic Neurons, Mary Elizabeth Muench

Master's Theses

No abstract provided.

The Interaction Of O6-Benzylguanine And Streptozotocin In The Inactivation Of O6-Methylguanine Dna Methyltransferase And The Reversal Of 1,3 Bis (2-Chloroethyl)-1-Nitrosourea Resistance, Upendra Kumar Marathi

Master's Theses

No abstract provided.

Central Serotonergic Stimulation Of Renin Secretion, Peter Andrew Rittenhouse

Dissertations

No abstract provided.

Synaptic Transmission In The Inferior Mesenteric Ganglion Of The Rabbit: An Electrophysiological And Immunohistochemical Study, Mark Alan Simmons

Dissertations

No abstract provided.

Isolated Frog Brainstem Technique: Analysis Of Neural Correlates Of Mating Calling And Possible Use In Drug Studies, David Douglas Schaffer

Dissertations

No abstract provided.

The Short And Long Term Effects Of Opiates On Myenteric Neurons, Peter J. Karras

Dissertations

No abstract provided.