Master of Science, The Ohio State University, 2018, Biomedical Engineering

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are lung disorders characterized by increased permeability of the alveolar barrier, resulting in fluid buildup and hypoxia. Patients with ALI or ARDS often require mechanical ventilation to displace occluded fluid and restore blood oxygenation. However, mechanical ventilation exposes alveolar and small airway epithelial cells to abnormal mechanical forces, which can exacerbate lung inflammation and injury, known as ventilator-induced lung injury (VILI). MicroRNAs, short RNAs with post-translational regulatory roles in gene expression, have emerged as promising therapeutic targets to protect against VILI. MicroRNAs 146a and 155 have been implicated in innate immunity, and shown to modulate inflammatory response during simulated lung injury . Delivery of microRNA cargos is critical for clinical translation into future VILI therapy. Endogenous extracellular vesicles (EVs) have emerged as potential drug carriers capable of delivering microRNAs of interest. To study EV-mediated delivery of microRNA-146a, A549 epithelial cell or differentiated THP-1 macrophage monocultures were incubated with either EVs containing pre-miR-146a or scramble gene, or reduced-serum media for 24 hours. MicroRNA expression levels were evaluated via qRT-PCR. EVs delivered pre-miR-146a into A549 and THP-1 cell cocultures, then oscillatory pressure (20 cmH2O, 0.2Hz) was applied for 16 hours. Secretion of interleukin (IL)-1ß, IL-6, and IL-8 was quantified via ELISA. MicroRNA-146a was overexpressed in monocultures of A549 and PMA-differentiated THP-1 cells. In cocultures with applied oscillatory pressure, dampening of IL-1ß and IL-6 secretion was inconclusive. Secretion of IL-8 significantly increased between pressure and no-pressure groups, with EVs potentially increasing pro-inflammatory response. Relative fold-change in cytokine secretion between treatment groups did not change. Overexpression of microRNA-146a (open full item for complete abstract)

Committee: Samir Ghadiali (Advisor); Joshua Englert (Committee Member) Subjects: Biomedical Engineering

Doctor of Philosophy, The Ohio State University, 2022, Biomedical Engineering

Extracellular vesicles (EVs) are naturally derived lipid membrane vesicles that are released by different cell types into the extracellular environment, and they play a crucial role in cell-to-cell communication and mirror specific molecular cues characteristic of the donor cell. EVs have emerged as promising delivery vehicles for therapeutic applications, due to their long-term stability in biofluids and systemic circulation, ability to penetrate biological barriers (e.g., cytoplasmatic membrane), low immunogenicity, exceptional biocompatibility, and ability to transport and deliver a variety of therapeutic agents. Therefore, while naturally derived EVs have shown to favor targeting towards specific cells/tissues, studies have evaluated the ability to introduce extrinsic properties to EVs such as surface modification with specific targeting ligands to enhance preferential EV uptake, as well as tailoring of their molecular cargo, maximizing thus therapeutic efficiency. The first chapter of this dissertation discusses the properties of these natural carriers and the different strategies that have been used to produce engineered EVs. The second chapter illustrates the development and implementation of engineered EVs as novel non-viral gene delivery systems to deliver anti-inflammatory molecular cargo with a therapeutic effect on inflammatory conditions. Similarly, the following chapter describes the fabrication of engineered EVs loaded with anti-inflammatory cargo and functionalized on the surface with targeting ligands to selectively deliver therapeutic payloads to the inflamed lung with the ability to reduce inflammation both in vitro and in vivo. The last chapter describes the development and implementation of designer EVs loaded with reprogramming transcription factors that can be effectively transferred and overexpressed by aortic valve tissue from patients that underwent valve replacement due to aortic stenosis, and their ability to induce cell reprogramming o (open full item for complete abstract)

Committee: Natalia Higuita-Castro (Advisor); Devina Walter (Committee Member); Daniel Gallego-Perez (Committee Member) Subjects: Biomedical Engineering

Doctor of Philosophy in Clinical-Bioanalytical Chemistry, Cleveland State University, 2019, College of Sciences and Health Professions

Ribonuclease L (RNase L) mediates interferon (IFN) function during viral infection and cell proliferation. RNase L deficient mice are heavier and have more lipid accumulation in the liver tissues compared to wide type mice under the same condition, suggesting that RNase L might mediate lipid homeostasis. The first part of the dissertation focuses on investigating the role of RNase L in lipid homeostasis. By using RNase L gene knockout mice with C57BL/6 background, we found a novel role of RNase L in lipid homeostasis through upregulating the rate-limiting enzymes that are essential for fatty acid and cholesterol syntheses. The excess amount of lipids is synthesized continuously, which leads to the development of Non-Alcoholic Fatty Liver Disease (NAFLD). Tissue distribution reveals that RNase L is highly expressed in the lung and other organs. However, the physiological roles of RNase L in the lung are largely unknown. In the second part of the dissertation, we found that lipopolysaccharide (LPS)-induced acute lung injury (ALI) was remarkably intensified in mice deficient RNase L compared to wild type mice under the same conditions. Furthermore, we found that RNase L mediated the TLR4 signaling pathway and regulated the expression of various pro- and anti-inflammatory genes in the lung tissue and blood. Most importantly, RNase L function in macrophages during LPS stimulation may be independent of the 2-5A system. These findings demonstrate a novel role of RNase L in the immune response via an atypical molecular mechanism. In the third part of the dissertation, an LC-MS/MS assay was developed and fully validated for the rapid quantitative measurement of GSK3 inhibitors, a promising therapeutic treatment for acute myeloid leukemia (AML). This assay has been applied for the measurement of GSK3 inhibitors in mice plasma and can be used for the preclinical and clinical study of the drugs.

Committee: Aimin Zhou (Committee Chair); David Anderson (Committee Member); Mekki Bayachou (Committee Member); Yana Sandlers (Committee Member); Bin Su (Committee Member); Yuping Wu (Committee Member) Subjects: Analytical Chemistry; Biochemistry; Biology; Molecular Biology

Doctor of Philosophy, Case Western Reserve University, 2018, Physiology and Biophysics

Peripheral organ injuries serve as potent stimuli for the immune system, triggering local inflammatory activation that can become increasingly amplified as the injury progresses, this in turn can lead to a severe systemic immune activation, which wreaks havoc over physiologic function. This is exemplified by lung injury, which can induce failure of multiple organ systems, or cause profound disruptions to brain function. When lung injury occurs in perinatal settings it may induce developmental impairments that last into adulthood. Here, using an experimental model of lung injury I investigated the mechanisms responsible for altering brainstem control of cardiorespiratory function in neonatal and adult rats. In neonatal rats, I determined that when lung injury is induced just before a transition period for the neural control of breathing (spanning P11-15), it promotes: i) an increase to the number of apnea directly preceded by a sigh, and ii) depression of viscerosensory synaptic transmission to 2nd-order neurons located in the nucleus tractus solitarii (nTS). This depression occurs through a postsynaptic mechanism that increases the contribution of Ca2+-impermeable (CI) AMPA receptors, and is mediated by the immune response to lung injury; minocycline, an inhibitor of microglia/macrophage activation, prevented the lung injury dependent increase in post-sigh apnea and the CI-AMPAR mediated synaptic depression. In rat-pups that were injured just after the transition period, viscerosensory synaptic transmission was also depressed, but occurred in a CI-AMPAR independent manner that contrastingly was presynaptically mediated. Thus, discrete mechanisms are responsible for these synaptic changes. In adult rats, where lung injury also increased the frequency of post-sigh apnea, I determined a novel immune-to-brain communication (I¿Bc) pathway utilized by the injury, which involves the glial-barrier separating the area postrema (a circumventricular organ) from the imm (open full item for complete abstract)

Committee: Frank Jacono M.D. (Advisor); George Dubyak Ph.D. (Committee Chair); Corey Smith Ph.D. (Committee Member); Thomas Dick Ph.D. (Committee Member); Roberto Galan Ph.D. (Committee Member) Subjects: Biophysics; Neurobiology; Physiology

PhD, University of Cincinnati, 2017, Medicine: Molecular and Developmental Biology

p16, a critical regulator of cellular proliferation and senescence, is deregulated in the majority of adult malignancies. Inactivation of p16, most commonly by promoter methylation, is an early event in the pathogenesis of lung cancer and is observed in the bronchial epithelium of smokers before the advent of histological features of carcinogenesis. This suggests that p16 functions to regulate epithelial repair and suppress cancer initiation in response to injury induced by smoking. The most well established p16 function is in suppression of cell cycle progression through regulation of the G1/S checkpoint. The classic paradigm is that p16 exerts its cell cycle regulatory functions through activation of the downstream effector Retinoblastoma (RB1). However, unlike p16, RB1 loss is frequently observed in only one adult tumor, small cell lung cancer (SCLC). Despite its well established characterization as a tumor suppressor, there is minimal knowledge about how p16 functions to block transformation. The studies in this dissertation were thus designed to investigate the role of p16 in regulation of lung epithelial cell growth and transformation in the context of lung injury and oncogenic stress caused by RB1 deficiency. We demonstrate that p16 is induced in RB1 deficient lung epithelial cells in vivo. Despite p16 induction, RB1 deficient cells do not undergo senescence. Instead, p16 promotes the survival of RB1 deficient cells and protects them against DNA damage. Additional p16 loss resulted in increased propensity to immortalization and subsequent transformation of RB1 deficient cells and increased incidence of tumors with aggressive metastases in vivo. To investigate the role of p16 in the context of DNA damage in the lung in vivo, p16 proficient and deficient mice were treated with bleomycin. p16 loss resulted in a significant increase in lung injury with aberrant epithelial repair characterized by abnormal localization of proximal bronchiolar epithelial cells linin (open full item for complete abstract)

Committee: Kathryn Wikenheiser-Brokamp M.D. Ph.D. (Committee Chair); Paul Andreassen Ph.D. (Committee Member); Chunying Du Ph.D. (Committee Member); Timothy Lecras Ph.D. (Committee Member); John Shannon Ph.D. (Committee Member) Subjects: Molecular Biology

Doctor of Philosophy, The Ohio State University, 2016, Integrated Biomedical Science Graduate Program

Influenza A virus is a readily transmissible respiratory pathogen that remains a significant threat to human health. Annual influenza epidemics are responsible for roughly 3 to 5 million cases of severe illness and more than 300,000 deaths/year worldwide. Additionally, the emergence of novel pandemic strains has the potential to cause devastating loss of life. Treatments for influenza infection, including vaccination and antiviral therapy, have limited utility. Vaccination plays a pivotal role in preventing influenza infection, but several issues arise related to vaccine uptake, distribution, and production. Moreover, a recent meta-analysis determined that antiviral drugs do very little to prevent influenza-related hospitalizations. Thus, there is a need for new therapeutics that can treat late-stage, severe influenza infection. In severe cases, primary influenza infection can lead the development of pulmonary edema and hypoxemia: key features of acute lung injury (ALI). Influenza infection gives rise to ALI via two mechanisms: 1) The disruption of normal ion transport in the distal lung leading to pulmonary edema; and 2) The induction of an over-robust immune response leading to tissue damage. We have previously shown that Influenza-induced ALI in C57BL/6 mice (WT mice) was associated with increased Cl- secretion via the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel expressed on cells of the distal lung. Interestingly, C57BL/6-congenic mice that are heterozygous for the F508del mutation in CFTR (HET mice), which exhibit a 50% reduction CFTR expression and CFTR-mediated Cl- transport, experienced a significant attenuation in ALI. Thus, the aim of these studies was to identify various factors within the HET model that dictate the beneficial phenotype. Attenuated ALI was alveolar macrophage (AM) dependent and was not linked to alterations in viral replication between strains. Also, HET AMs displayed an anti-inflammatory phenotype compared to (open full item for complete abstract)

Committee: Ian Davis (Advisor) Subjects: Biomedical Research

Doctor of Philosophy, The Ohio State University, 2015, Biophysics

This report hence examines the expression and function of IkappaBzetain lung inflammation. We start by exploring the regulation of IkappaBzeta in lung epithelial cells, followed by evaluating its role in three different models of lung inflammation: allergy, infection and mechanical injury. In conclusion, this report highlights the expression, function and regulation of IkappaBzetain in various models of lung inflammation including allergy, infection and mechanical injury.

Committee: Mark Wewers (Advisor) Subjects: Immunology

PhD, University of Cincinnati, 2013, Medicine: Pathobiology and Molecular Medicine

Abstract: Pneumonia is a primary complication and a leading cause of death for burn patients. Conventional antimicrobial strategies to combat pneumonia in burn patients and others have become less effective due to the emergence of multi-resistant organisms. At the inception of these studies, we aimed to develop a mouse model of post thermal injury pneumonia, to interrogate perturbations of pulmonary immune function and to test alternative therapeutic strategies. We found that burn injury induced a surprising paradoxical resistance to pulmonary infection that developed with time after injury. Instead of abandoning the model, we postulated that an understanding of the mechanisms of induced resistance could be exploited for improving strategies for the treatment of pneumonia. Our studies revealed that the protection from infection following thermal injury was dependent on a systemic increase in functionally enhanced neutrophils, which followed a surge in circulating G-CSF. G-CSF stimulation of the marrow resulted in highly specific activation of STAT3 in mature myeloid and myeloid precursors in the bone marrow, and a reprioritization of hematopoiesis, in which myeloid cell production increased at the expense of other lineages. The myeloid shift in the bone marrow and the systemic increase in neutrophils were temporally related to the acquisition of resistance to infection. Finally, we determined that exogenous administration of G-CSF was sufficient to recapitulate the hematopoietic changes and protection from infection. From this study we concluded that the G-CSF STAT3 axis protects the host from post injury pulmonary infection. In parallel experiments, we also explored the hypothesis that keratinocyte growth factor (KGF), which is known to be induced following injury of the skin, plays an important role in burn induced protection. The concept that KGF might be `arming' cells and enhancing resistance to infection was based in part on prior work from our laboratory demo (open full item for complete abstract)

Committee: Francis McCormack M.D. (Committee Chair); George Deepe M.D. (Committee Member); Daniel Healy Pharm.D. (Committee Member); Dennis McGraw M.D. (Committee Member); Kathryn Wikenheiser-Brokamp M.D. Ph.D. (Committee Member) Subjects: Surgery

PhD, University of Cincinnati, 2001, Medicine : Environmental Health Sciences

Acute lung injury is a common, severe respiratory syndrome that can develop from indirect and direct insults to the lung. Despite extensive research since the initial description of acute lung injury over 30 years ago, questions remain about the basic pathogenic mechanisms and their relationship to therapeutic strategies. Microarray analysis during the progression of nickel-induced acute lung injury revealed an overall pattern of gene expression consistent with several pathogenic processes, including oxidative stress. NO can generate oxidative stress, either alone or by the formation of other reactive nitrogen species with reactive oxygen species. NO synthesis can be inhibited by binding of hepatocyte growth factor-like protein to the receptor tyrosine kinase Ron. Mice with a targeted deletion of the tyrosine kinase domain of Ron (Ron tk-/-) overproduce NO in response to endotoxin, therefore, these mice were used to examine whether the overproduction of NO would increase susceptibility to nickel-induced acute lung injury. In response to nickel, Ron tk-/- mice displayed decreased survival time, accelerated cytokine expression, augmented serum nitrite levels, and earlier onset of perivascular edema. To examine whether inhibiting NO would increase resistance to nickel-induced acute lung injury, NO synthesis was inhibited using NG-nitro-L-arginine methyl ester (L-NAME). Sixty-percent of L-NAME treated mice survived nickel-induced acute lung injury versus 5% of saline-treated mice. L-NAME treatment attenuated cytokine expression, polymorphonuclear cell infiltration and protein levels in lavage, and restored cyclin dependent kinase like 2 (Cdkl2) and surfactant gene expression. Restoration of surfactant gene expression is consistent with enhanced survival and attenuation of cytokine expression. These findings indicate that Ron is a key regulator of NO during nickel-induced acute lung injury and that NO inhibition may be protective by restoration of surfactant gene express (open full item for complete abstract)

Committee: George Leikauf (Advisor) Subjects:

PhD, University of Cincinnati, 2008, Medicine : Pathobiology and Molecular Medicine

Airway remodeling is associated with the vast majority of lung diseases including chronic obstructive pulmonary disease, asthma, and lung cancer. Epithelial regeneration is a key component in airway remodeling after injury. Accordingly, deregulated epithelial cell proliferation, survival, and differentiation play a prominent role in the pathogenesis of chronic lung disease. The lung epithelium is composed of specialized cell types that result from coordinate regulation of progenitor/stem cell proliferation and differentiation. The retinoblastoma gene product (Rb) regulates both proliferation and differentiation, and is inactivated in nearly all cases of lung cancer strongly implicating Rb as a critical regulator in the lung epithelium. The objective of this dissertation project was to test the hypothesis that Rb is essential for proper lung epithelial repair after injury. Rb ablation was targeted to the lung epithelium using a tetracycline regulated Cre/LoxP system, and epithelial injury was induced with naphthalene to mimic human lung disease. These studies demonstrate that although Rb is not required for establishing and maintaining epithelial quiescence during homeostasis, Rb is essential for establishing quiescence during epithelial repair after injury. Rb ablation during development and in the postnatal lung had similar effects providing evidence that timing of Rb loss was not critical to the phenotypic outcomes, and that the injury induced phenotype was not secondary to compensatory alterations occurring during development. After establishing this critical role for Rb in epithelial remodeling after a single episode of injury, Rb function was assessed in a chronic injury model to more closely mimic human lung disease. These studies led to the discovery of previously unknown effects of the highly utilized naphthalene injury model; namely naphthalene injury results in altered epithelial composition and subsequent inflammation. Importantly, Rb dependent sustained (open full item for complete abstract)

Committee: Kathryn Wikenheiser-Brokamp M.D./Ph.D. (Advisor); David Askew Ph.D. (Committee Member); Greg Boivin D.V.M. (Committee Member); Thomas Korfhagen M.D./Ph.D. (Committee Member); Erik Knudsen Ph.D. (Committee Member) Subjects: Molecular Biology; Oncology; Pathology

MS, University of Cincinnati, 2006, Medicine : Environmental Health

Acute lung injury is the rapid onset of lung dysfunction with many causes. One such cause is occupational and/or environmental exposure to respirable metal particulates. Surfactant protein B (SFTPB) is found in the alveoli of the lungs and is known to be a critical gene for normal lung function. Metallothionein-1 (MT1) is a protein that forms bonds with certain metal ions and has long been used as a biomarker for metal exposure. The overall goal of this study is to determine how nickel affects surfactant and induces acute lung injury. Three specific objectives were: 1) to generate dose-response (death) curves for various metals on mouse-lung-epithelial cells, 2) to measure the extent of Sftpb and Mt1 transcription, and 3) a transcriptome-wide scan of gene transcription using microarray analysis that can confirm the hypothesis that transcriptional control of select genes is critical for host defense or susceptibility to nickel induced acute lung injury. Nickel was determined to decrease SFTPB and increase MT1, and many other transcripts were also affected and analyzed to gain insight as to how acute lung injury manifests itself in host organisms. Some of these other transcripts include thioredoxin reductase, EGLN1 with prolyl 4-hydroxylase, HIF-1α, ubiquitin, and the receptor for advanced glycation end products. The relationships found between the expression of these genes suggest that transcriptional regulation of their proteins is a determining factor in whether organisms develop acute lung injury, and whether these organisms can then survive acute lung injury.

Committee: Dr. George Leikauf (Advisor) Subjects:

MS, University of Cincinnati, 2004, Allied Health Sciences : Transfusion and Transplantation Medicine

BACKGROUND: Transfusion-Related Acute Lung Injury (TRALI), one of the most common noninfectious, life-threatening implications of blood transfusion,is associated with the administration of blood that contains anti-MHC (Major Histocompatibility Complex) antibodies. To date, theories regarding TRALI pathogenesis are based on in vitro animal studies and human clinical case studies. Lack of controlled in vivo animal experiments has made it difficult to test theories of TRALI pathogenesis as well as possible therapeutic interventions. Our objective was to develop an in vivo murine model that shares features with human TRALI. METHODS: BALB/c (H-2d) mice were injected with 34-1-2s, a murine IgG2a anti-H-2d (D/K) monoclonal antibody (mAb). Hypothermia which reflects the development of shock) was measured by rectal thermography over the next 2 hours and dyspnea was measured by noninvasive barometric plethysmography. RESULTS: Hypothermia and dyspnea were rapidly induced in BALB/c mice but not in congenic H-2k controls. Pathologic changes in the lungs after anti-MHC mAb challenge included an increase in vascular permeability that led to pulmonary edema and protein leak into the alveolar spaces. In addition, a neutrophilic alveolar infiltrate developed within two hours of challenge. This evolved into a mononuclear alveolar infiltrate by 24 hours after challenge. Pretreatment with anti-FcγRII/III mAb to block FcγRII/III receptors, gadolinium to deplete macrophages, anti-granulocyte mAb to deplete granulocytes, or platelet activating factor (PAF), histamine or leukotriene antagonists, inhibited the induction of hypothermia and dyspnea. CONCLUSIONS: These results suggest that IgG, FcγRIII, granulocytes, macrophages, PAF, histamine, and leukotrienes are important in anti-MHC antibody induction of shock and pulmonary dysfunction. This animal model should be useful for determining the pathogenic mechanisms of TRALI and for identifying potential therapeutic interventions.

Committee: Dr. Brian Susskind (Advisor) Subjects: Health Sciences, General

Master of Science, The Ohio State University, 2009, Molecular, Cellular, and Developmental Biology

The cells of the innate immune system are responsible for an organism's first line of defense against various pathogens. Cells such as macrophages and neutrophils are capable of detecting the presence of a bacterial, viral, fungal, or protozoan pathogen through specialized Toll-like receptors on the plasma membrane. These receptors, when activated, initiate an inflammatory response mediated by various kinases, catalytic and regulatory proteins, and ubiquitin ligases, resulting in the activation of several transcription factors, including NF-κB. It is through this signaling cascade that the cells are able to initiate phagocytosis to destroy the pathogen, and release pro-inflammatory cytokine molecules to activate other immune cells and propagate the immune response. However, unregulated inflammation results in several serious human inflammatory diseases including sepsis and sepsis-related disorders such as acute lung injury. Several decades of failed clinical trials have led to the search for alternative therapies. Flavonoids, a class of polyphenolic plant compounds, are reported to be potent anti-inflammatory agents in vitro and in vivo, but their molecular and physiological mechanisms are still largely unknown. Apigenin is a member of the flavonoid family, and has similarly demonstrated anti-inflammatory properties. In these experiments it is shown that apigenin inhibits transcriptional activation of NF-κB and subsequent release of pro-inflammatory cytokines TNFα, IL-1β, and IL-8 in response to bacterial lipopolysaccharide (LPS) stimulation. Apigenin did not modulate degradation of the NF-κB inhibitor IκB or interfere with binding of NF-κB with DNA. However, apigenin modulated phosphorylation of NF-κB's p65 subunit via indirect inhibition of the IKKβ kinase. Apigenin was effective in reducing TNFα production mediated by several different Toll receptor ligands. Naringenin (a structurally similar compound), as well as glycosylated forms of apigenin failed to modulate (open full item for complete abstract)

Committee: Andrea Doseff (Advisor); Erich Grotewold (Committee Member); Mark Parthun (Committee Member) Subjects: Molecular Biology

Doctor of Philosophy, The Ohio State University, 2008, Pharmacy

The long-term goal of this study is to identify a potential innovative therapeutic target to prevent or treat Acute Respiratory Distress Syndrome (ARDS), a condition associated with systemic inflammation and characterized by extensive lung epithelial damage leading to protein enriched fluid influx into the lung alveolar space and compromised ventilation [1, 2]. The rapid progression of acute lung injury at the onset of ARDS is one of the reasons responsible for the high mortality of ARDS [3]. A variety of strategies to treat and manage ARDS has been extensively investigated. However, patient survival has not been improved. Based on the previous work of our laboratory and numerous studies that identify the cell survival phosphatidylinositol 3'-kinase (PI3K)/Akt pathway as a vital survival axis in the lung epithelium, we focused on this pathway as a molecular target to prevent lung epithelium dysfunction [4-6]. Phosphatase and Tensin homolog deleted on chromosome Ten (PTEN) is a phosphase that is known to be a negative regulator of the PI3K/Akt survival pathway by dephosphorylation of PI(3,4,5)P3 at the 3 position in the inositol ring thereby inactivating this second messenger [7, 8]. PTEN is enriched in the lung epithelium as observed in our preliminary data. The Knoell laboratory previously reported that activation of the PI3K/Akt pathway promotes lung epithelial cell survival during inflammatory stress [4]. Based on this, we hypothesized that inhibition of PTEN by specific PTEN inhibitors would be a rational therapeutic strategy to facilitate normal lung epithelium cell function under stress conditions. The PTEN inhibitor, bisperoxovanadium, was first reported in 2004 documenting PTEN target specificity in cell culture models [9]. In our study, the same PTEN inhibitor and a related analogue were utilized and studied for their in vitro and in vivo potential to inhibit PTEN, activate the PI3K/Akt signaling axis and/or other downstream signaling pathways of PTEN, and (open full item for complete abstract)

Committee: Daren Knoell PharmD (Advisor); James Dalton PhD (Advisor); Thomas Schmittgen PhD (Committee Member); Duxin Sun PhD (Committee Member); Susheella Tridandapani PhD (Committee Member); Normand St-Pierre PhD (Other) Subjects: Pharmaceuticals; Pharmacology