Biological Phenomena, Cell Phenomena, and Immunity Commons^™

Role Of Chronic Stress-Induced Neuroinflammation In Rodent Locus Coeruleus Physiology And Anxiety-Like Behaviors, Arthur Anthony Alfonso Reyes

Graduate School of Biomedical Sciences Theses and Dissertations

The locus coeruleus (LC), the primary site of brain norepinephrine (NE), is a key anatomical brain region implicated in the stress response. Stress is a neuroendocrine physiologic response to a stressor that promotes organism survival through adaptive change and restoration of homeostasis. The central stress response, which drives behavioral and physiological change, is primarily mediated by activating the hypothalamic-pituitary-adrenal (HPA) axis. While advantageous in the short term, chronic stress exposure can lead to HPA axis and LC dysregulation, which are thought to contribute to the etiology of anxiety disorders. Previous studies demonstrate the effects of acute stress in increasing LC …

Immunomodulatory Effects Of Resolvin D2 In A Model Of Infection, Prem Yugandhar Kadiyam Sundarasivarao

Graduate School of Biomedical Sciences Theses and Dissertations

Dysregulated hyperinflammatory host immune response to underlying bacterial infections is a characteristic of sepsis. In sepsis, bacteria often trigger abnormal hyperinflammatory responses which can cause multiple organ failure and if sustained can lead to an immunosuppressive phase where the host is susceptible to secondary infections caused by opportunistic bacteria like Pseudomonas aeruginosa (P. aeruginosa). In our studies, we used a 2-hit model of cecal ligation and puncture (CLP) followed by P. aeruginosa secondary lung infection to investigate cellular and molecular mechanisms in the beneficial action of resolvin D2 (RvD2). Resolvins of the D-series are a group of fatty acids known …

The Effects Of Specialized Pro-Resolving Mediator Lipoxin A4 On Pseudomonas Aeruginosa Biofilms And Interactions With Monocytes, Julianne M. Thornton

Graduate School of Biomedical Sciences Theses and Dissertations

Pseudomonas aeruginosa (P. aeruginosa) is an opportunistic pathogen known as a major cause of hospital-acquired secondary infections, commonly causing chronic respiratory infections in immunocompromised individuals, especially those with cystic fibrosis, and often found in wound infections. P. aeruginosa uses the quorum sensing pathway to readily form protective biofilms, which reduce the efficacy of antibiotics and access by host immune cells to eradicate the pathogen. Specialized pro-resolving mediators (SPMs) are lipids endogenously produced by the host immune response to infection to aid in infection resolution. One SPM, Lipoxin A4 (LxA4), has been shown to be a robust quorum sensing inhibitor.

The …

Med13 Degradation Defines A New Receptor-Mediated Autophagy Pathway Activated By Nutrient Deprivation, Sara E. Hanley

Graduate School of Biomedical Sciences Theses and Dissertations

Cells are exposed to an enormous amount of diverse extracellular cues but have a limited arsenal of weapons for protecting and maintaining homeostasis. To overcome these restrictions, nature has engineered proteins that have multiple functions. The pleiotropy of using one protein to carry out a variety of functions allows cells to rapidly execute tailored responses to a diverse set of signals. The Cdk8 kinase module (CKM) is a conserved detachable unit of the Mediator complex predominantly known for its role in transcriptional regulation. The CKM is composed of four proteins, the scaffolding proteins Med13 and Med12, as well as the …

Contact Normalization And The Role Of Maackia Amurensis Seed Lectin As A Novel Chemotherapeutic And Antiviral Agent, Stephanie A. Sheehan

Graduate School of Biomedical Sciences Theses and Dissertations

Cells communicate with each other to coordinate tissue function and homeostasis. Diseases including cancer, arthritis, and acute respiratory disease syndrome (ARDS) require a breakdown in this intercellular communication. For example, cancer progression is suppressed by junctional communication between nontransformed and transformed cells. This process is called contact normalization. Junctional communication must be disrupted to enable transformed cells to grow into malignancies. However, the junctions and mechanisms by which nontransformed cells normalize cell behavior have not been clearly defined. My project aimed to identify junctions and elucidate mechanisms underlying contact normalization. We discovered that cadherins, specifically N-cadherin, form junctions that enable …

Cyclin C Determines Cell Fate In Response To Oxidative Stress And Proteasome Inhibition, David C. Stieg

Graduate School of Biomedical Sciences Theses and Dissertations

In response to various sources of cellular stress, the coordination of intracellular events is necessary to elicit the appropriate molecular response. In particular, the reprogramming of gene expression by stress-specific transcription factors drives the activation of signaling pathways, triggering either cell survival or regulated cell death pathways. The Cdk8 kinase module (CKM) is a highly conserved transcriptional regulatory complex with a role in this decision. The CKM is composed of Cdk8, its activating partner cyclin C, and two scaffold proteins, Med12 and Med13. The CKM is a detachable subunit of the Mediator complex, which interacts with RNA polymerase II to …

The Autoimmune System: The Effect Of Physiological Stressors On Autoantibody Glycosylation And Fidelity Of Autoantibody Profiles, Rahil Kheirkhah

Graduate School of Biomedical Sciences Theses and Dissertations

The presence of thousands of autoantibodies (aABs) in the human sera is typical, and therefore it is possible to identify an aAB profile for each individual. In the first part of this thesis, we will show the cerebrospinal fluid also exhibits an extraordinarily complex immunoglobulin G aAB profile that is composed of thousands of aABs. We show that the pattern of expression of individual aABs in CSF closely mimics that in the blood, indicative of a blood-based origin for CSF aABs. In addition, using longitudinal serum samples obtained over a span of nine years, we show remarkable stability in aAB …

Natural Autoantibodies: Origin, Function And Utility For Diagnosis Of Disease, Abhirup Sarkar

Graduate School of Biomedical Sciences Theses and Dissertations

Autoantibodies (aAbs) by the simplest definitions have been described as antibodies against self-antigens and were exclusively associated with autoimmune diseases. Eventually, studies demonstrated that they are abundant in the blood of all human sera, regardless of age, gender, or the presence or absence of disease, and were thus named as ‘natural autoantibodies’. The underlying reason for their ubiquity has remained elusive, but we have hypothesized that they are responsible for clearing blood-borne cell and tissue debris generated under conditions of health and disease. To test this, we chose to use two widely different disease model systems, namely neurodegenerative diseases and …

Inhibition Of Ribosome Biogenesis Through Genetic And Chemical Approaches, Leonid Anikin

Graduate School of Biomedical Sciences Theses and Dissertations

In order to maintain the ability to generate proteins, proliferating cells must continuously generate ribosomes, designating up to 80% of their energy to ribosome biogenesis (RBG). RBG involves transcription of rDNA by RNA polymerases I (Pol I) and III (Pol III), expression of approximately 80 ribosomal proteins, and assembly of these components in a process referred to as ribosome maturation. During maturation, the Pol I transcribed 47S pre-rRNA undergoes a number of processing events, while simultaneously interacting with processing factors and ribosomal proteins that drive pre-ribosome assembly. Inhibition of RBG has become one of the pursued targets for cancer therapy …

Characterization Of Malt1 Inhibitors And Their Effect On Leukemic Cell Growth Properties, Christina Snyder

Graduate School of Biomedical Sciences Theses and Dissertations

Leukemia is the most common childhood cancer, with a combined 40,000 predicted new cases in the United States in 2016 [8]. The two most common subtypes are acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) [9-11]. The commercially available inhibitor of Bruton’s tyrosine kinase (BTK) has shown promising results in clinical trials for CLL because of the importance of BCR signaling in CLL [12-15]. Recent studies suggest that the outgrowth of BTK inhibitor resistant clonal cells in some CLL patients results in a treatment-refractory phenotype [16-18]. MALT1, a protein involved in BCR activation of the NF-κB pathway that functions …

Utility And Origin Of Blood-Based Autoantibodies For Early Detection And Diagnosis Of Neurodegenerative Diseases, Cassandra Demarshall

Graduate School of Biomedical Sciences Theses and Dissertations

Autoantibodies are self-reactive antibodies that have been widely implicated as causal agents of autoimmune diseases. They are found in the blood of all human sera, regardless of age, gender, or the presence or absence of disease. While the underlying reason for their ubiquity remains unknown, it has been hypothesized that they participate in the clearance of blood-borne cell and tissue debris generated in both healthy and diseased individuals on a daily basis. Although much evidence supports this debris clearance role, recent studies also suggest a causal role for autoantibodies in disease. My thesis work has focused on this "cause and/or …

The Effects Of Lipoxin A4 (Lxa4) On Neutrophil Biology In Sepsis, Benedict Wu

Graduate School of Biomedical Sciences Theses and Dissertations

During sepsis, neutrophils are inappropriately activated and have prolonged lifespans, thus becoming dysfunctional. Excessive neutrophil activation can lead to tissue injury while neutrophil dysfunction can lead to decreased free radical production and reduced phagocytosis, preventing the host from clearing preexisting infections. Lipoxin A4 (LXA4) is a specialized pro-resolution mediator which reduces neutrophil migration and expression of proinflammatory mediators. Intact neutrophil functions are critical for the host to efficiently clear invading pathogens. The effects of LXA4 on neutrophil function in sepsis have not been established. Using the cecal ligation and puncture (CLP) model of sepsis, LXA4 administered 1 h after sepsis …