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Anti-Cancer Effects Of Garcinol In Pancreatic Cancer Transgenic Mouse Model, Nadia Saadat

Wayne State University Dissertations

Adenocarcinoma of pancreas is recognized for its poor prognosis, as it progresses asymptomatically and is rarely diagnosed at early stage. According to American cancer society pancreatic cancer, it has lowest survival rate in all cancer types, with less than 6% five year survival rate. Surgical resection is only possible for 20% of diagnosed cases and current chemotherapy has only 15% response rate. Even the most favored drug, Gemcitabine, increases survival time only by a few months, depending on the stage at diagnosis. Some bioactive food components or nutraceuticals have shown chemopreventive and chemotherapeutic effects without added side effects. Garcinol is …

Role Of Ubiquitin E3 Ligase Breast Cancer Associated Gene 2 (Bca2) In Sumoylation, Fareea Khaliq

Honors College Theses

As the occurrence of breast cancer increases around the world, the need for new therapeutic medicine becomes more vital to sustain the population. In order to accomplish this, specific mechanisms need to be understood to gain a perspective on the overall process of breast cancer development. One mechanism that is being researched is SUMOylation. The SUMOylation reaction uses small ubiquitin-like modifier (SUMO) proteins, which act as a type of post-translational modification that is necessary in order to preserve protein homeostasis and regulate cellular processes including apoptosis, cell proliferation, and response to stress. The SUMOs attach to a target protein through …

Physical Activity And Exercise During Adolescence And Young Adulthood Can Act As Preventative Measures Against The Development Of Osteoporosis In Elderly People, Christine C. Center

Honors College Theses

Osteoporosis, “the silent killer,” is responsible for 8.9 million annual fractures. Although not bound to these factors, osteoporosis typically targets females that are post-menopausal and have a family history of the disease. Osteoporosis is caused by a decrease in bone mass density. Physical activity and exercise and often spoken about when the topic of osteoporosis is discussed because of the impact they have on maintaining bone mass density in an effort to delay osteoporosis. This paper first provides an overview of osteoporosis, explanation of methods of diagnosing osteoporosis, risk factors, complications and treatment for osteoporosis. Topics covered include, bone mass …

The Role Of Oxidative Stress In The Pathogenesis Of Epithelial Ovarian Cancer, Nicole Marie King

Wayne State University Dissertations

Ovarian cancer is the leading cause of death from gynecologic malignancies yet the underlying pathophysiology is not clearly established. The disease is usually diagnosed in the advanced stage and carries a poor prognosis. The 5-year survival rate is greater than 75% if diagnosis of the cancer occurs at an early stage; however, this rate drops to 20% when the tumor has spread beyond its origin. Thus, a method for early detection is critically needed, which can help prolong, or even save lives. Currently, an effective screening test for ovarian cancer is lacking. Many tests have been evaluated but have been …

Investigating Hfq-Mrna Interactions In Bacteria, Martha Audra Faner

Wayne State University Dissertations

Regulatory RNAs (sRNAs) are essential for bacteria to thrive in diverse environments and they also play a key role in virulence [11]. Trans-sRNAs affect the stability and/or translation of their target mRNAs through complementary base-pairing. The base-pairing interaction is not perfect and requires the action of an RNA binding protein, Hfq. Hfq facilitates these RNA-RNA interactions by stabilizing duplex formation, aiding in structural rearrangements, increasing the rate of structural opening, and/or by increasing the rate of annealing [18-21]. Hfq has two well characterized binding surfaces: the proximal surface, which binds AU rich stretches typical of sRNAs, and the distal surface, …

Characterization Of High-Voltage-Activated Calcium Channels In Retinal Bipolar Cells, Qi Lu

Wayne State University Dissertations

Retinal bipolar cells, conveying visual information from photoreceptors to ganglion cells, segregate visual information into multiple parallel pathways through their diversified cell types and physiological properties. Voltage-gated Ca²⁺ channels could be particularly important underlying the diversified physiological properties of different BCs. In this dissertation, I investigated the high-voltage-activated (HVA) calcium current in retinal bipolar cells in mice. In the first part of my dissertation, I characterized multiple bipolar cell-expressing GFP and/or Cre transgenic mouse lines. In the second part of my dissertation, by performing whole-cell patch-clamp recordings, I examined the electrophysiological properties of HVA calcium currents among CBCs and …

Mechanisms Of Cytokine-Induced Metabolic Dysfunction Of The Pancreatic Beta-Cell, Abiy Mussa Mohammed

Wayne State University Dissertations

MECHANISMS OF CYTOKINE-INDUCED METABOLIC DYSFUNCTION OF THE PANCREATIC BETA-CELL

by

ABIY MUSSA MOHAMMED

August 2013

Advisor: Dr. Anjaneyulu Kowluru

Major: Pharmaceutical Sciences

Degree: Doctor of Philosophy

Type I diabetes is characterized by an absolute insulin deficiency due to loss of pancreatic â-cell mass by autoimmune aggression. During the progression of the disease proinflammatory cytokines such as IL-1â, TNFá and INFã are secreted by infiltrated and activated T-cells and macrophages which ultimately damage the pancreatic â-cell. However, the signaling mechanisms involved in cytokine-induced damage are only partially understood. Phagocyte-like NADPH oxidase [NOX2] has been shown to play regulatory roles in the …

The Drosophila Interactions Database: Integrating The Interactome And Transcriptome, Thilakam Murali

Wayne State University Dissertations

In this thesis I describe the integration of heterogeneous interaction data for Drosophila into DroID, the Drosophilainteractions database, making it a one-stop public resource for interaction data. I have also made it possible to filter the interaction data using gene expression data to generate context-relevant networks making DroID a one-of-a kind resource for biologists. In the two years since the upgraded DroID has been available, several studies have used the heterogeneous interaction data in DroID to advance our understanding of Drosophila biology thus validating the need for such a resource for biologists. In addition to this, I have identified …

Thick Ascending Limb Nitric Oxide Production And Inhibition Of Nkcc2 Activity Are Impaired In Angiotensin Ii-Induced Hypertension, Vanesa Daniela Ramseyer

Wayne State University Dissertations

Cardiovascular disease is the leading cause of death in the US. Hypertension, which affects about 30 % of the US population, is an important risk factor in the development of this disease. Inappropriately elevated sodium reabsorption by the kidney contributes to hypertension; therefore, studying the mechanisms that lead to enhanced sodium transport is important in understanding this pathology. The thick ascending limb (THAL) reabsorbs 30% of the filtered sodium chloride load. Nitric oxide (NO) produced by NO synthase type 3 (NOS3) increases cyclic GMP (cGMP) and inhibits THAL transport by reducing Na/K/2Cl cotransporter type 2 (NKCC2) activity. Interestingly, in angiotensin …

Single-Molecule Studies Of Local And Global Nucleic-Acid Dynamics, Eric Muthuri Patrick

Wayne State University Dissertations

Nucleic acids undergo both global and local conformational changes that are important for their function. Structural studies have over the decades been invaluable in elucidation of various biomolecular mechanisms, hence contributing significantly to the understanding of biological events. However, a clear understanding of how molecules function in the cellular context requires investigation of their interconversion between multiple conformations, including mapping the folding landscape and any coupled changes in conformation. Work in this thesis focuses on fluorescence experiments, mainly at a single-molecule level to investigate such processes.

First, a novel single-molecule approach is described focusing on local dynamics within nucleic acids …

Overcoming Tumor Drug Resistance By Activating Amp-Activated Protein Kinase And Destabilizing Oncoproteins, Min Shen

Wayne State University Dissertations

Although considerable progress has been achieved in the field of cancer therapeutics, primary or acquired drug resistance remains a fundamental cause of therapeutic failure in cancer therapy. Among different mechanisms characterized that are responsible for tumor drug resistance, there is increasing evidence suggesting that dysregulation of gene expression, especially oncogene or tumor suppressor gene expression, at either gene transcription or protein synthesis level, can contribute to the drug-resistant phenotype. AMP-activated protein kinase (AMPK) is a well-known major cellular energy sensor, which negatively regulates metabolic pathways such as protein synthesis, fatty acid oxidation and glucose consumption. Activation of AMPK may suppress …

Impact Of Cryoablation On Tumor Immunity, Jesse Veenstra

Wayne State University Dissertations

Background and Objectives: Percutaneous cryoablation is a minimally invasive procedure for tumor debulking, which has the potential to initiate or amplify tumor immunity through the release of tumor-associated antigens and endogenous danger signals. However, enhanced immunity is rarely observed in treated patients, suggesting the need for mechanistic analysis. The goal is to determine how cryoablation affects tumor specific immunity and if the response can be improved through exogenous TLR9 stimulation.

Methodology: We evaluated anti-Her2/neu immunity following cryoablation in wt BALB/c and tolerant NeuT mice inoculated with neu or Her2 expressing mammary tumors TUBO and D2F2/E2 respectively. Mice were treated with …

Roles Of Neuregulin1 In Neuromuscular Junction Development, Jiajing Wang

Wayne State University Dissertations

Neuromuscular junction (NMJ) development is a multistep process mediated by coordinated interactions between nerve terminals, target muscles, and peri-synaptic glial cells, and thus requires reciprocal signals derived from every cell type. Neuregulin1s (NRG1s) are a family of predominantly neuronal growth and differentiation factors that are important for many aspects of nervous system development. In this thesis, both the effects of NRG1 on NMJ development and reciprocal effects of neurotrophic factors on NRG1 expression were studied as a means to define the complex regulatory communication at the NMJ. Using the chicken embryo as a model, methods were developed to study the …

Towards Personalized Medicine Using Systems Biology And Machine Learning, Calin Voichita

Wayne State University Dissertations

The rate of acquiring biological data has greatly surpassed our ability to interpret it. At the same time, we have started to understand that evolution of many diseases such as cancer, are the results of the interplay between the disease itself and the immune system of the host. It is now well accepted that cancer is not a single disease, but a “complex collection of distinct genetic diseases united by common hallmarks”. Understanding the differences between such disease subtypes is key not only in providing adequate treatments for known subtypes but also identifying new ones. These unforeseen disease subtypes are …

Mechanisms Mediating Modulation Of The Cardiopulmonary Chemoreflex Control Of Regional Sympathetic Outputs By Adenosine A1 And A2a Receptors In The Nts, Zeljka Minic

Wayne State University Dissertations

ABSTRACT

by

ZELJKA MINIC

August 2013

Advisor: Dr. Tadeusz J. Scislo

Major: Physiology

Degree: Doctor of Philosophy

Adenosine is an important neuromodulator of cardiovascular control at the level of the nucleus of the solitary tract (NTS) where cardiovascular and other autonomic reflexes are primarily integrated. Levels of adenosine increase in the NTS during life threatening hypotension, ischemia and hypoxia. Adenosine may modulate cardiovascular reflexes to correct hemodynamic imbalance, acting via A₁ and A_2a receptors which inhibit and facilitate neurotransmitter release, respectively. Previous studies from our laboratory showed that NTS A₁ adenosine receptors inhibit the arterial baroreflex whereas …

Platyrrhine Phylogenetics With A Focus On Callitrichine Life History Adaptations, Natalie Mae Jameson

Wayne State University Dissertations

The life history of a species is highly impacted by their reproductive strategy. In my dissertation I address the changing reproductive strategies in callitrichine New World monkeys and their genetic underpinnings using a phylogenetic approach. The necessity for a resolved phylogeny is universal to any comparative genomic study. Here we have constructed a reliable phylogenetic framework from which reproductive strategy could be studied in callitrichines. First, to determine the most recent common ancestor of Anthropoid primates we took a phylogenomic approach, using the publicly available whole genome sequences of 17 mammal species. With high confidence, we determined here that Tarsier …

Landscape Characteristics Of Upland Sandpiper Habitat In Michigan, Jacob Lawrence Korte

Wayne State University Theses

Grassland bird populations have declined across North America due to habitat loss but at a disproportionately higher rate in the midwestern United States, where extensive coverage of grasslands and other open land ecosystems have been converted to other land cover types. The upland sandpiper (Bartramia longicauda Bechstein, UPSA) is a migratory, area-sensitive, terrestrial shorebird that breeds in grasslands and other open land ecosystem types across their North American range. Although breeding habitats of the Great Plains contain the greatest concentrations of this species, anthropogenic openings such as hayfields and pastures serve as surrogate habitat elsewhere, as do remnant patches …

Evaluation Of Effectiveness Of Classroom-Based Nutrition Intervention On Changes In Eating Behavior In African American Parents/Caregivers And Their Children., Nesrine Akil

Wayne State University Theses

Although obesity rate has increased steadily over the past 20 years in the US, a 2006 report showed that the obesity rate is expected to continue to rise, with 13.9% of children between the ages of 2 to 5 years are considered overweight. However, 26.2% were considered at risk of becoming overweight. The parents/caregivers are the key players for developing their children's healthy or unhealthy eating habits since they are the specific determinants of food selection, serving structured meals and being the role models to their children by eating the same food offered themselves. This reflects the parents' significant roles …

Influence Of Mechanical Cues And The Extracellular Matrix On Cell Migration Patterns And The Proliferation Rates Of Cells, Tara Shane Alger

Wayne State University Theses

The mechanical environment of a cell and its tissue can impact multiple biological processes including development, wound healing, and metastasis. Specific cellular behaviors influenced by the mechanical microenvironment include differentiation, morphology, apoptosis, migration, and proliferation. In this thesis I have focused specifically on the effect of environmental stiffness and applied mechanical forces on cellular migration and proliferation, respectively. Using two different applications, both tailored to evaluate the mechanical forces alone on cellular behavior, I attempted to simulate the mechanical composition of the in vivo tissue microenvironments in vitro using polyacrylamide hydrogels. To test whether cells maintain a mechanical memory for …

Extending Lifespan Using Various Prolongevity Interventions And Their Effects On Enhancing Dna Repair Activity, Sonia Ahmad

Wayne State University Theses

Aging is not a disease; it causes a decrease in the physiological functions of cells, tissues, and organs. Aging has been considered as one of the biggest risk factors for the development of various diseases such as cancer, type-2 diabetes, obesity, atherosclerotic cardiovascular diseases, and neurodegeneration. Numerous studies have shown that lifespan can be extended in mice by genetic, dietary, and pharmacological interventions. A few prolongevity interventions currently being studied include: the drug rapamycin, that has been found to inhibit mTOR expression and exhibit anticancer properties; reduced caloric intake, a broadly acting dietary intervention for preventing carcinogenesis, and ultimately extending …

Effect Of Folate Deficiency And Aging On Mtor Signaling Network In The Liver Of Dna Polymerase B Haploinsufficient Mice, Amanda Lynn Arrabi

Wayne State University Theses

EFFECT OF FOLATE DEFICIENCY AND AGING ON mTOR SIGNALING NETWORK IN THE LIVER OF DNA POLYMERASE B HAPLOINSUFFICIENT MICE

by

AMANDA ARRABI

August 2013

Advisor: Dr. Ahmad R. Heydari

Major: Nutrition and Food Science

Degree: Masters of Science

The interaction between the dietary nutrients and the human genome causes some alterations in the molecular pathways that could significantly impact the development of cancer. The main approach to such concerns is to closely observe how the diet modifies the gene expressions that control several cellular processes in the human body. Folate deficiency (FD) has established an important role in modulating the …

Selenium Supplementation Increases Antioxidant Response In Vitro, Yasmin Fakhereddin

Wayne State University Theses

Reactive oxygen species and free radicals are associated with the negative effects of aging. Enzymatic and non-enzymatic mechanisms can defend cell structures from free radical damage. Selenium is an essential trace element necessary for cellular functions in the human body. A positive correlation between low serum selenium levels with the morbidity and mortality of a range of cancers has been illustrated in numerous studies. Glutathione Peroxidase catalyzes a reaction in which H2O2 oxidizes the reduced form of GSH and forms H2O. NADPH further reduces GSSG, the oxidized structure of glutathione, in a reaction catalyzed by glutathione reductase. Tissue culture was …

Investigating The Metal Binding Affinity Of Bacterial Zinc Transporters: Zupt And Truncated Znta (Znta-Pina), Fei Nie

Wayne State University Theses

Zinc is essential trace elements for all living organisms and serves as cofactor and structural cofactors for more than 300 enzymes. ZupT is one of the members of ZIP super family of transporter proteins, which were identified as iron and zinc transporter in Eukaryotes at first. However, recent evidence showed that some of members can also transport other metal ions, such as manganese or cadmium, and ZIP proteins also exist in bacteria. ZupT is responsible for zinc uptake in E. coli; however, its full metal selectivity is not yet characterized. In addition, the mechanism of transport is also unknown. Therefore, …

Characterizing Cyclin J By Identifying Conserved Protein-Protein Interactions, Phillip Jacob Selman

Wayne State University Theses

Cyclins are proteins that bind to Cyclin-dependent kinases, or Cdks, through a conserved domain called the Cyclin Box. Many Cyclins regulate the cell cycle. A few Cyclins impact cellular processes outside of the cell cycle. Also, a few Cyclins have poorly understood functions.

Cyclin J is a member of the Cyclin superfamily of proteins. Cyclin J is conserved among all metazoans, but is presently not well understood. All the research done on Cyclin J has been done in Drosophila.

Its mRNA is present in the early embryo, then disappears, only to reappear in adult females. When probing protein extracts with …

Nutritional Status In A Cohort Of Hemodialysis Patients Receiving Tocotrienol Supplementation, Rajeev Shahani

Wayne State University Theses

Kidney disease is defined by a loss of kidney function over time [1]. It is expressed in terms of glomerular filtration rate at five stages calculated by the MDRD formula [5]. The fifth stage (<15 mL/min/1.73m2) is designed as end stage renal disease requiring renal replacement therapy in the form of hemodialysis [5]. This requires the use of an artificial kidney (dialyzer) to filter out by-products from the blood for excretion [8]. The issue arises when toxin accumulation due to decreased renal function, dialytic factors such as incompatible dialyzer membranes reacting with blood, and co-morbid conditions such as infection or diabetes mellitus [3]. This increases inflammation within the body, leading to a negative nutrient/energy balance, resulting in a loss of body mass thereby increasing the mortality risk [10]. Tocotrienols (T3), a more potent and underutilized form of Vitamin E, are being administered to attenuate this increase in inflammation via supplementation in addition to food intake. In order to attend to this issue, the nutritional status was assessed utilizing three measures: examining nutrient intake profiles (while supplementation was taken into consideration), obtaining anthropometric findings of body mass index, and analyzing biochemical profiles of serum albumin and pro-inflammatory markers (i.e. IL-6). This data was obtained via a randomized, double blind, placebo-controlled study of 81 dialysis patients. At two times over the course of 16 weeks, blood collection for serum albumin and inflammatory markers was analyzed and dietary intake was assessed using 24-hour diet recalls and Nutritionist Pro software. Statistical analyses of paired t-tests and correlation studies revealed no significant differences between the two groups later showing no noticeable effect of T3 supplementation. Reasoning may be multifactorial such as underestimation of food intake, transcription of diet recalls may not be truly representative, or T3 supplements may not have had an effect on the nutritional statuses. It may be beneficial for patients to receive more extensive nutritional counseling as opposed to nutritional supplementation to ensure compliancy with recommended intakes.

Regulation Of Nuclear Localization Of The Sole Sumo-Conjugating Enzyme, Ubc9, Palak Sekhri

Wayne State University Theses

The covalent and reversible conjugation of small ubiquitin-like modifier (SUMO) proteins to hundreds of different cellular proteins is catalyzed by a cascade of enzymes including an E1-activating enzyme (SAE1/SAE2), an E2-conjugating enzyme (Ubc9) and multiple E3 ligases. As the only E2 enzyme for SUMO-conjugation, Ubc9 localizes mainly in the nucleus and plays an essential role in regulation of many cellular processes including cell cycle progression through mitosis, cell migration, genome stability, stress response, transcription, and nuclear transport in eukaryotic cells. It is hypothesized that the nuclear localization of Ubc9 is required for efficient sumoylation inside the nucleus because both the …

Impact Of Folate Depletion On Expression Of Folate Metabolizing Enzymes, Yizhen Wu

Wayne State University Theses

Folate is a water-soluble vitamin B that plays a critical roles in the de novo nucleotide synthesis, DNA repair, DNA methylation, and cellular growth. By involved in the one-carbon metabolic pathways, folate influences the thymidine monophosphate (dTMP) and the purine nucleotides synthesis, consequently affect the DNA synthesis and repair. Through the one-carbon pathway, the folate level also influences the DNA methylation, consequently affect the gene expression.

In this study, we inspected the change of gene expression of 14 genes which are related to the folate metabolism in two different cell lines. One is MEF cell line and the other one …

Development Of Peptide Inhibitors Targeting Clostridium Difficile Toxins A/B And Characterizing The Regulatory Role Of A Putative Negative Regulator Tcdc In Clostridium Difficile Toxin Gene Expression, Sanofar Jainul Abdeen

Wayne State University Dissertations

Clostridium difficile infections cause one of the most common and vital hospitalacquired

diseases often associated with broad-spectrum antibiotic usage. TcdA and TcdB

are the key virulence factors involved in major patho-physiology. While standard

antibiotics provide some respite, due to the high relapse rates and the emergence of more

severe disease presentations, antibiotics alone have often proven to be suboptimal.

Therefore there is a desperate need to develop an effective non-antimicrobial

therapeutics. Part of this work focuses on identification and further characterization of

peptide therapeutic that target the major virulence factor TcdA/TcdB. Towards

development of mechanistic-based anti-toxin agent, phage display was …

Characterization Of Antimicrobial-Resistant Staphylococcus Spp. In Food Animals And Retail Meat, Kanika Bhargava

Wayne State University Dissertations

Antimicrobial resistance in Staphylococcus spp. is a worldwide epidemic concern in hospital and community settings. Food animals and retail meat are important reservoirs of these pathogens that can pose potential threat to humans. In this dissertation, we aimed to investigate the molecular epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant Coagulase-negative Staphylococci (MRCoNS) in food animals and retail meat to provide insight into the role of agricultural environment in transmitting bacteria of human clinical significance. Furthermore, the potential application of phytochemicals as antimicrobials and antimicrobial adjuvants to control MRSA infections was explored.

CoNS recovered from food animals were characterized by …

How Atomic Level Interactions Drive Membrane Fusion: Insights From Molecular Dynamics Simulations, Navendu Bhatnagar

Wayne State University Dissertations

This project is focused on identifying the role of key players in the membrane fusion process at the atomic level with the use of molecular dynamics simulations. Membrane fusion of apposed bilayers is one of the most fundamental and frequently occurring biological phenomena in living organisms. It is an essential step in several cellular processes such as neuronal exocytosis, sperm fusion with oocytes and intracellular fusion of organelles to name a few. Membrane fusion is a frequent process in a living organism but is still not fully understood at the atomic level in terms of the role of various factors …