Medicine and Health Sciences Commons^™

Macrophages And Associated Inflammation Differentially Impact Obesity, Colorectal Cancer And Obesity-Enhanced Colorectal Cancer, Jackie Bader

Theses and Dissertations

Colorectal Cancer (CRC) is the third-most common malignancy for men or women, with chronic inflammation considered as a primary risk factor. Obesity is also considered a chronic inflammatory disease and is associated with increased CRC incidence. Further, obesity and CRC occur in men and women differently with the highest incidence of either disease found in men, suggesting that female sex hormones may play a protective role in inflammatory diseases. Macrophages can promote inflammation and are a driving force in obesity-associated metabolic dysfunction. Conversely, macrophages also contribute to pro-tumoral responses including, proliferation, angiogenesis and tissue remodeling. This heterogeneity of macrophage behavior …

Role Of Epigenome And Microbiome In Endocannabinoid-Mediated Regulation Of Inflammation During Diet-Induced Obesity, Kathryn Miranda

Theses and Dissertations

Obesity is an inflammatory disease involving accumulation of adipose tissue, gut microbiota dysbiosis, and over-activation of the endocannabinoid system (ECS). Mechanisms involved in ECS regulation of obesity-induced inflammation are not well understood. Presented here are three chapters involving microRNA (miR) regulation of inflammatory adipose tissue macrophages (ATM) during high-fat diet (HFD)-induced obesity and cannabinoid receptor-mediated regulation of gut microbiota dysbiosis.

ATMs are innate immune cells that drive chronic low-grade inflammation during obesity. Polarization between pro-(M1) and anti-(M2-like) inflammatory phenotypes influence insulin sensitivity and energy expenditure; however, the mechanisms involved are unclear. In study one, we characterized miRs involved in ATM …

Characterization Of The Role Of Insulin-Like Growth Factor Binding Protein 7 (Igfbp7) Using A Genetic Knockout Mouse Model, Maaged A. Akiel

Theses and Dissertations

In the US, the incidence and mortality rates of hepatocellular carcinoma (HCC) are alarmingly increasing since no effective therapy is available for the advanced disease. Activation of IGF signaling is a major oncogenic event in diverse cancers, including HCC. Insulin-like growth factor binding protein-7 (IGFBP7) inhibits IGF signaling by binding to IGF-1 receptor (IGF-1R) and functions as a potential tumor suppressor for hepatocellular carcinoma (HCC). IGFBP7 abrogates tumors by inducing cancer-specific senescence and apoptosis and inhibiting angiogenesis. We now document that Igfbp7 knockout (Igfbp7-/- ) mouse shows constitutive activation of IGF signaling, presents with pro-inflammatory and immunosuppressive microenvironment, and develops …

Post-Tbi Hippocampal Neurogenesis In Different Tbi Models, Kaushal S. Patel

Theses and Dissertations

Traumatic brain injury (TBI) leads to short-term and long-term consequences that can cause many different life-long disorders. Studies of TBI have generally focused on the acute stage; however, it is now becoming important to investigate chronic responses following TBI as clinical reports of dementia and cognitive impairments have been linked to a history of TBI. Recent data have established that cognitive function is associated with hippocampal neurogenesis. Chronic injury induced changes in the brain may affect this endogenous process. Chronic responses following TBI include cell death pathways and inflammatory responses that are persistent in the brain for months to years …

The Effect Of Arsenic On Type 2 Diabetes And Inflammation, Kayla Penta

Theses and Dissertations

Arsenic, a ubiquitous environmental contaminant, has been shown to cause a number of health effects. At high concentrations the inorganic form is a well-known toxin, but at lower concentrations the effects range from various cancers, to cardiovascular disease and type 2 diabetes. At higher concentrations of arsenic (500- 1000μg/L) there have been epidemiological studies conducted demonstrating an increased risk in the development of type 2 diabetes with this exposure. At lower levels of arsenic exposure (<500 μg/L) the epidemiological results are inconclusive. Arsenic is also an immunotoxicant, meaning that it will cause changes in the immune response. The changes in the immune response will vary depending on a number of variables, including amount of arsenic exposure, forms of exposure and route of exposure. We wanted to determine if arsenic could modulate the immune system, and if this change could lead to an increase in susceptibility to type 2 diabetes development. We chose to examine this in C57BL/6 and db/+ mice – two non-susceptible strains. After 8 weeks (4 weeks old to 12 weeks old) of low dose inorganic arsenic exposure (50 μg/kg or 500 μg/kg) we evaluated changes in body composition, glucose tolerance and immune response. We saw that there were differences based on sex, genotype and treatment group present after the 8-week treatment period in body composition, while there were minimal changes in glucose tolerance. Finally, the immune response showed great variability depending on sex, genotype and treatment group. This project has demonstrated that while we are trying to compare differences in in vivo and epidemiological studies to find a link between arsenic and type 2 diabetes, there may be deeper levels of complications based on individual variability to arsenic exposure.

Mcp-1 In Colorectal Cancer: Benefits Of Exercise, Jamie Lee Mcclellan

Theses and Dissertations

The etiology of colon cancer is a complex phenomenon that involves both genetic and environmental factors. However, only about 20% have a familial basis with the largest fraction being attributed to environmental causes that can lead to chronic inflammation. Tumors associated macrophages drive the pro-inflammatory response in the tumor micro-environment and are associated with poor prognosis in certain cancers. Monocyte chemoattractant protein 1 (MCP-1) is thought to be the most important chemokine for recruitment of macrophages to the tumor microenvironment. In chapter 1, we examined the timing and magnitude of the intestinal inflammatory cytokine response in relation to tumorigenesis in …

Transformation Of Human Mast Cells By Interferon-Gamma And The Potential Role Of Myeloid Derived Suppressor Cells In Mastocytosis., Sahar Lotfi-Emran

Theses and Dissertations

Mast cells respond to a variety of signals, are associated with both increased inflammation and regulation of the immune response, and are able to interact with a variety of hematopoietic and non-hematopoietic cells. The majority of the work that highlights mast cell pleiotropic abilities has been completed in murine models. Though these models have significantly advanced our understanding of what mast cells can do, they cannot inform us as to what mast cells actually do in human beings. The goal of this dissertation is to assess fully mature, primary human mast cell function beyond the well-defined type 1 hypersensitivity function …

The Role Of Microrna In Staphylococcal Enterotoxin B-Induced Inflammation And Acute Lung Injury, Roshni Rao

Theses and Dissertations

Staphylococcal enterotoxin B (SEB) is a potent activator of the Vβ8+T-cells leading to the proliferation of nearly 30% of the T-cell pool. As a consequence, excessive amounts of cytokine mediators are released leading to extensive tissue damage and sometimes toxic shock and death. Due to the ease with which SEB can be aerosolized anddisseminated, it is considered a biological weapon. In the current study, we investigated the pro-inflammatory effects of SEB in two mouse models of acute inflammatory lung injury. Specifically, while inflammatory cues are known to elicit changes in key transcriptional factors and gene expression, we explored for the …

The Role Of Nitric Oxide Dysregulation In Tumor Maintenance, Christopher Rabender

Theses and Dissertations

The inflammatory nature of the tumor microenvironment provides a cytokine and chemokine rich proliferative environment. Much of the responsibility of this environment is due to the production of Reactive Oxygen Species (ROS). These studies examined the proliferative rich tumor environment from a new perspective of Nitric Oxide Synthase (NOS) dysregulation. NOS’s have the ability to become uncoupled and generate superoxide in lieu of nitric oxide (NO). A requirement of NOS for the production of NO is the cofactor tetrahydrobiopterin (BH4) and when it is missing NOS becomes uncoupled and turns into a peroxynitrite synthase. Here I demonstrate that NOS is …

Osteopontin Expression During The Acute Immune Response Mediates Reactive Synaptogenesis And Adaptive Outcome, Julie Chan

Theses and Dissertations

Traumatic brain injury (TBI) is a worldwide epidemic as the number of victims living with the resulting cognitive and physical impairment continues to rise, principally due to limited treatment options which fail to address its multifaceted sequelae. By approaching TBI therapy from a molecular standpoint, we have the opportunity to develop a better understanding of the mechanisms which prevent effective recovery. With this information, we can move toward the identification of novel therapeutic treatments which target specific molecules to improve patient outcome following TBI. Here, we have focused on the therapeutic potential of osteopontin (OPN), an extracellular matrix (ECM) protein …

Targeting The Endocannabinoid System To Reduce Inflammatory Pain, Sudeshna Ghosh

Theses and Dissertations

The endogenous cannabinoids (endocannabinoids) anandamide (AEA) and 2-arachidonylglycerol (2-AG) exert their effects predominantly through cannabinoid CB1 and CB2 receptors, but these actions are short-lived because of rapid hydrolysis by fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively. Selective inhibition of either enzyme elevates CNS levels of the appropriate endocannabinoid and produces analgesic effects with fewer psychomimetic side effects than Δ9-tetrahydrocannabinol (THC), the primary active constituent of marijuana. While cannabinoid receptor agonists and FAAH inhibitors reliably produce anti-inflammatory and anti-hyperalgesic effects in the carrageenan test and other inflammatory pain models, much less is known about the consequences of inhibiting …

Targeting The Endocannabinoid System To Reduce Nociception, Lamont Booker

Theses and Dissertations

Pain of various etiologies (e.g., visceral, inflammatory) can be a debilitating disorder that presents a problem of clinical relevance. While it is known that ∆9-tetrahydrocannabinol (THC) the primary psychoactive constituent found in marijuana produces analgesia in various rodent models of pain, its pharmacological properties are overshadowed by its psychomimetic effects. THC is the primary phytocannabinoid found in marijuana though other prevalent constituents such as the phytocannabinoids (e.g., cannabidiol (CBD), cannabinol (CBN), cannabichromene (CBC), tetrahydrocannabivarin (THCV)) may possess antinociceptive actions without the psychomimetic effects associated with THC. Indeed, these phytocannabinoids act upon the endocannabinoid system (ECS) that is comprised of the …