Biological Phenomena, Cell Phenomena, and Immunity Commons^™

Evaluating The Therapeutic Potential Of Geranylgeranyl Diphosphate Synthase Inhibitor, Ram2061, In Myeloma Bone Disease, Molly Muehlebach

Theses & Dissertations

Multiple myeloma (MM) is a hematological malignancy of the plasma cells which often results in lytic bone disease. Myeloma bone disease (MBD), characterized by diffuse osteopenia, bone lesions, or pathological fracture, results from MM mediated promotion of osteoclast resorption and dual inhibition of bone formation, drastically reducing bone strength and integrity. Development of MBD is known to significantly impact patient quality of life and increase risk of mortality. Considering that up to 80-95% of MM patients are expected to develop bone disease post-initial MM diagnosis, there is a significant need within this population for therapeutics which address both MM disease …

Understanding The Role Of Mastl In Colon Homeostasis And Colitis-Associated Cancer Development, Kristina Pravoverov

Theses & Dissertations

Colitis-associated cancer (CAC) is the most devastating complication of longstanding inflammatory bowel disease (IBD). Understanding the mechanisms underlying the switch from damage-repair to dysplasia in IBD is critical for identifying novel therapies to facilitate mucosal healing while mitigating CAC risk. Microtubule-associated serine-threonine kinase-like (MASTL), though crucial in cell growth and repair, is upregulated in sporadic colorectal cancer and CAC. This study sought to delineate the role of MASTL in colitis and CAC development.

First, we examined whether MASTL is associated with colitis and recovery. Review of publicly available data found significant elevation of MASTL and interleukin (IL)-22 in biopsies from …

Erα As A Modulator Of The Sle1b Lupus Susceptibility Locus And B Cell Receptor Signaling, Jared H. Graham

Theses & Dissertations

Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by loss of immune tolerance and the production of anti-nuclear autoantibodies. 90% of lupus patients are women, and this sex bias is due to the actions of estrogens, which promote lupus pathogenesis. Our lab has shown that estrogen receptor alpha (ERα) mediates the effect of estrogens in lupus and that ERa acts in a B cell intrinsic manner to promote the development of autoantibodies and SLE. Genetic factors also contribute to lupus. One major lupus susceptibility locus, Sle1, controls loss of tolerance and autoantibody development as well as immune cell …

Exosomes Secreted Under Hypoxia Enhance Stemness In Ewing’S Sarcoma And Transform Microenvironment Cells, Matthew J. Kling

Theses & Dissertations

Intercellular communication between tumor cells and stroma within the hypoxic microenvironment promote aggressiveness and poor patient prognoses in ways that remain unclear. Here we show that hypoxic Ewing’s sarcoma (EWS) cells release exosomes that promote sphere formation, a stem-like phenotype, in EWS cells by enhancing survival and a cancer-associated phenotype in fibroblasts (CAFs). Given that hypoxia enriches for stem-like cells, we exposed EWS cells to hypoxia and hypoxic EWS-derived exosomes and assessed the stem cell phenotype. Hypoxia and hypoxic EWS-derived exosomewere found to enhance TIC formation in vitro and in vivo by reprogramming EWS cells. Analysis of the hypoxic exosomal …

Alcohol Drives Oxidation-Dependent Desensitization Of Airway Cilia Motility Responsiveness, Michael Price

Theses & Dissertations

Alcohol abuse, which can impair clearance of pathogens and debris from the airway, is associated with an increase in complications and a higher mortality rate during the progression of pneumonia. With prolonged alcohol exposure, mucociliary clearance (MCC), which depends on the coordinated beating of cilia, is dysfunctional. Effective MCC relies on cAMP-dependent protein kinase (PKA) activation of ciliary beat frequency (CBF). PKA activation and stimulation of CBF are blunted with chronic exposure to alcohol. This phenomenon is known as alcohol-induced ciliary dysfunction (AICD). Previous studies have shown that concomitant feeding of mice with alcohol and antioxidants prevents AICD, suggesting a …

Muc4 Based Immunotherapy For Pancreatic Cancer, Kasturi Banerjee

Theses & Dissertations

Pancreatic Cancer (PC) is a lethal disease claiming approximately 45000 lives in the US in 2018, and it establishes an elaborate immunosuppressive tumor microenvironment that aids in disease pathogenesis. Immunotherapy has emerged as a strategy to target tumor cells by reprogramming patient’s immune system. Challenges present in PC immunotherapy are: i) identifying a tumor-associated antigen that could be targeted, ii) identifying adjuvants that could efficiently deliver antigens, iii) eliciting robust anti-tumor responses and iv) overcoming peripheral tolerance and immunosuppression elicited by the tumor.

Firstly, we detected circulating autoantibodies to MUC4 present in PC patients and observed that IgM autoantibodies to …

Regulatory Roles Of Mical-L1 And Ehd1 In Cell Signaling And Mitosis, James B. Reinecke

Theses & Dissertations

Membrane trafficking is a basic cell biological process that controls the distribution of proteins and lipids. Our lab is particularly interested in delineating the cellular functions as well as the molecular mechanisms that regulate the C-terminal Eps15 Homology Domain (EHD) protein family of adenosine-5’-triphosphatases in mammalian cells. EHD1-4 are ubiquitously expressed in mammalian tissues and serve partially overlapping but also distinct functions in regulating membrane shaping and fission along the endocytic pathway. Specifically, EHD1 is recruited to tubular recycling endosomes (TREs) by Molecule Interacting with CasL Like-1 (MICAL-L1) and facilitates TRE fission and release of cargo from the perinuclear endocytic …

The Role Of Glutaminase 1 In Hiv-1 Associated Neurocognitive Disorders And In Brain Development, Yi Wang

Theses & Dissertations

Glutaminase is the enzyme that converts glutamine into glutamate, which serves as a key excitatory neurotransmitter and one of the energy providers for cellular metabolism. Glutamate is essential for proper brain functioning but at excess levels, it is neurotoxic and has a key role in the pathogenesis of various neurodegenerative diseases, including HIV-1 associated neurocognitive disorders (HAND). However, the detailed mechanism of glutamate-mediated neurotoxicity remains unclear. In part I, we identified the regulation of glutaminase 1 (GLS1) in the central nervous system (CNS) of HAND animal models including HIV-Tat transgenic (Tg) mouse and HIVE-SCID mouse, since GLS1 is the dominant …