Master of Science, The Ohio State University, 2023, Psychology

Background: Lung cancer is a product of inflammation and a dysfunctional immune system, and depression has similar dysregulation. Depression disproportionately affects lung cancer patients and has been shown to be significantly associated with systemic inflammation responses. Independently, systemic inflammation, depression, and the depressive symptom trajectory are predictive of non-small cell lung cancer (NSCLC) survival, but the impact of comorbid depressive symptoms with high inflammation at diagnosis on the depressive symptom trajectory is unknown. Studied is the depressive symptom trajectory of four baseline depressive symptom/inflammation profile groups (LoDep/LoInf, LoDep/HiInf, HiDep/LoInf, HiDep/HiInf), with the hypothesis that patients with high depression and high inflammation at baseline would show a uniquely different trajectory of depressive symptoms, one that is elevated compared to all other groups, including patients with high depression but low inflammation. Methods: Newly diagnosed stage-IV non-small cell lung cancer (NSCLC; N=182) patients were enrolled (ClinicalTrials.gov Identifier: NCT03199651). Clinical characteristics, cell count, and albumin data for inflammation biomarker calculation were abstracted from patient electronic medical records from first clinic visit or soon thereafter. Linear mixed models were used to test for differences in the depressive symptom trajectory from diagnosis through 8 months for each baseline depressive symptom/inflammation profile group. Results: Linear mixed models confirmed a significant interaction between Profile 4 (HiDep/HiInf) and time (F(24,945) = -.04, p = .001), indicating Profile 4 (HiDep/HiInf) membership at diagnosis was a significant predictor of the depressive symptom trajectory in both the simple model and the model adjusting for significant sociodemographic and clinical covariates. Tests of this interaction were insignificant for all other profiles, including Profile 3 (HiDep/LoInf). Conclu (open full item for complete abstract)

Doctor of Philosophy, Case Western Reserve University, 2020, Organizational Behavior

Affective climate constitutes the collective mood of organizational members. A positive affective climate has been viewed as a prerequisite of a healthy organization in which employees can achieve individual and collective goals, and is associated with greater individual loyalty to the organization and improved team performance, among other positive organizational outcomes. Leaders are the architects of the affective climate in teams, and through the process of mood contagion, the moods of leaders typically exert an outsized influence on the moods of those that they lead. Inflammation-associated mood deterioration (IAMD) has been demonstrated under experimental conditions, and has been linked to an increased incidence of mood disorder symptomatology. Across two studies, I use agent-based modeling to model affective climate, and its potential degradation over time via IAMD, as an emergent phenomenon that can be generated through the interaction of team members based on simple local rules. I simulate an organizational environment in which tasks and social interactions represent affective events, resulting in subsequent affective responses in the form of altered mood states via mood contagion. In Study 1, by employing parametric sensitivity analyses and the criterion of generative sufficiency, I found that increases in focal leader IAMD resulted in affective climate degradation over time. Increases in focal leader IAMD also resulted in climates that were more variable over time, and for which a more pronounced differential in follower moods also drove climate degradation. Increasing the number of teams within the simulated environment buffered against climate degradation and produced climates that were relatively more stable. In Study 2, non-linear patterns in affective climate were observed which reflected variations in distance between teams interacting with the effects of IAMD on the focal leader over time, resulting in non-linear degradations of climate. Findings f (open full item for complete abstract)

PhD, University of Cincinnati, 2020, Medicine: Molecular, Cellular and Biochemical Pharmacology

Acute and chronic inflammation are reflected by systemically greater abundance of proinflammatory cytokines and increased infiltration and activation of immune cells in various tissues. In particular, cardiac dysfunction is a common ailment associated with both acute and chronic inflammatory states. As a fundamental component of innate immunity, macrophages play critical roles in both initiating and resolving inflammation in the heart. In fact, macrophages are prominent cells that drive septic cardiomyopathy in animal models; and human monocytes/macrophages secrete more inflammatory cytokines in type 2 diabetic patients and positively correlate with atherosclerosis severity. Secreted and transmembrane protein 1 (Sectm1, also referred to as K12) is a type 1 transmembrane protein. The knowledge of Sectm1 function in human diseases is currently limited to its role as an alternative CD7 ligand to stimulate T cell proliferation. Whether Sectm1 plays a role in normal macrophage biology and inflammatory diseases has never been investigated. In this dissertation, we observed that mRNA levels of Sectm1a (mouse homolog of human Sectm1) was significantly increased in early time points (peak at 6 h), but reduced at later time points in LPS-treated bone marrow-derived macrophages (BMDMs) and spleen of wild-type (WT) mice injected with LPS. To determine the role of Sectm1a in macrophage activation and inflammation-induced cardiac injury, we generated a Sectm1a-knockout (KO) mouse model in which LPS-induced cardiac injury and mortality were greatly augmented. Further analysis revealed that inflammatory macrophages in hearts of KO-LPS mice was greatly accumulated, compared to WT-LPS controls. In accordance to the activated macrophage phenotype, lack of Sectm1a dramatically increased the production of inflammatory cytokines (TNFa, IL-6, and IL-1ß) and MCP-1 levels both in vitro (BMDMs) and in vivo (in serum and myocardium) after LPS challenge. Moreover, we detected significantly (open full item for complete abstract)

Master of Science, The Ohio State University, 2017, Human Ecology: Human Nutrition

Genetic, dietary and inflammatory factors contribute to the etiology of major mood disorders (MMD), thus impeding the identification of specific biomarkers to assist in diagnosis and treatment. We tested the association of vitamin D and inflammatory markers in 36 adolescents with bipolar disorder (BD) and major depressive disorder (MDD) forms of MMD and without MMD (non-mood control). We also assessed the overall level of inflammation using a cell-based reporter assay for nuclear factor-kappa B activation and measuring antibodies to oxidized LDL. We found that these factors were similar between non-mood and MMD youth. To identify potential biomarkers, we developed a screening immunoprecipitation-sequencing approach based on inflammatory brain glia maturation factor beta (GMFß). We discovered that a homologue of GMFß in human plasma is low molecular weight vitamin D binding protein (DBP-L). DBP-L was 8 times more abundant in plasma of BD compared to control participants. DBP-L is a product of enzymatic cleavage, transforming DBP into a macrophage-activating factor. DBP levels in participants' plasma were validated using western blot because mono- and polyclonal ELISA did not recognize DBP-L. We found significantly increased levels of total DBP and DBP-L in BD compared to control participants. The DBP responds early to cellular damage by scavenging structural proteins and activating inflammatory cells. Our data suggest DBP and DBP-L as marker candidates of BD warranting their validation in a larger cohort of adolescent and adult MMD patients.

Doctor of Philosophy in Regulatory Biology, Cleveland State University, 2014, College of Sciences and Health Professions

Inflammation is an obligatory attempt of the host immune system to protect the body against infection. However, unregulated synthesis of pro-inflammatory products can have detrimental effects. Though mechanisms which contribute to inflammation are well appreciated, those that resolve inflammation are poorly understood. Therefore, understanding the molecular basis of such pathways will provide an entirely novel approach to treat and prevent inflammatory diseases. Transcript-selective translational control can regulate the expression of a set of inflammatory genes. We have identified one such mechanism in a novel animal model which relies on the abrogation of ribosomal protein L13a-dependent translational silencing by creating macrophage-specific L13a-knockout mice where resolution of inflammation is severely compromised. We have used these knockout mice to study two different kinds of inflammation: LPS induced systemic inflammation and dextran sodium sulphate (DSS) induced experimental colitis. Upon LPS induced endotoxemia, these mice displayed high mortality rates and severe symptoms of inflammation such as infiltration of immune cells in the peritoneum and major organs leading to tissue destruction. These animals also exhibited high serum levels of TNF-a, blood urea nitrogen (BUN), aspartate aminotransferase (AST) and several other markers of inflammation. Macrophages from these knockouts showed unregulated synthesis of several chemokines (e.g., CXCL13, CCL22, CCL8 and CCR3) and increased polysomal abundance of these mRNAs due to the abrogation of their translational silencing. Upon DSS induced colitis, these knockout mice demonstrated higher susceptibility to colitis displaying reduced survival, significant weight loss, enhanced rectal bleeding and diarrhea. Histopathology analysis of tissue sections from the knockouts showed disruption of epithelial crypts in the colon with infiltration of macrophages in colon and spleen sections. Additionally, elevated levels of (open full item for complete abstract)

Doctor of Philosophy, The Ohio State University, 2013, Integrated Biomedical Science Graduate Program

Stress is commonly considered to be immunosuppressive, but in some diseases states, such as asthma or infection, stress can be immunoenhancing. This immunoenhancement has been associated with immune cell glucocorticoid resistance that renders the cells insensitive to the anti-inflammatory effects of glucocorticoids. A unique murine social disruption stress paradigm, SDR, can model the stress-induced glucocorticoid resistance and exacerbation of inflammation, which can be relevant to inflammatory diseases in humans. In the context of SDR, stress enhances inflammation and delays resolution in an Aspergillus fumigatus (Af) allergic airway inflammation model. In stressed and Af challenged mice, gene expression data suggested increased inflammation (IL-1ß, TNF-a, GM-CSF) with histological data supporting that the increase was due to infiltrating inflammatory cells. Furthermore, stress and Af challenge most prominently increased granulocytes in the lung compared to controls. Bone marrow chimeras demonstrated that the increase in immune cells was bone marrow-derived, and that stress induced myeloid progenitor cell egress and trafficking to lung. Closer examination of the granulocytic population identified many as neutrophilic populations. Using the antibodies to CD16 and CD49d, several distinct neutrophil populations were visualized including apoptotic, mature, activated, or immature neutrophils. Stress and Af challenge significantly increased the immature neutrophil population in both the lung and blood. In the clinic, it has been shown that a rapid release of immature neutrophils from the bone marrow can occur during times of stress and immune challenge. The consequences of this state of neutrophilia on disease are still being determined, but it is known these neutrophils have a higher capacity to induce inflammation and exacerbate patient symptoms. In a second study, we examined the consequences of Y1 receptor (Y1R), ß-adrenergic receptor (ßAR), and IL-1 receptor t (open full item for complete abstract)

Master of Science, Miami University, 2024, Cell, Molecular and Structural Biology (CMSB)

This study aims to determine the effect of novel bioactive compounds from the Zingiberaceae family on inflammatory mediators, including pro-inflammatory cytokines and enzymes. To investigate the molecular mechanisms through which the Zingiberaceae bioactive components reduce inflammation, we employed a mouse model of 12-O-tetradecanoylphorbol-13-acetate (TPA) to induce skin inflammation. TPA-induced skin inflammation and weight increase is a widely recognized model for assessing the protective effects of dietary compounds against skin inflammation. In this study, there was a significant reduction in the average TPA-induced weight increase of ear punches treated with 6-paradol (3 μmol), yakuchione-A (2 μmol), and yakuchione-B (2 μmol). We measured ear thickness, topical application of 6-paradol (1.5 and 3μmol), 6-shogaol (3 μmol), oxyphyllacinol (2 μmol), yakuchione-A (2 μmol), and yakuchione-B (2 μmol) significantly inhibited ear thickening and edema. To explore the underlying mechanism of action of the bioactive compounds, we employed ELISA, qPCR, and IHC to determine the expression of pro-inflammatory cytokines and pro-inflammatory enzymes. The results from this study suggest that 6-paradol, 6-shogaol, oxyphyllacinol, yakuchione-A, and yakuchione-B inhibit TPA-induced skin inflammation.

Doctor of Philosophy, Case Western Reserve University, 2024, Pathology

The steroid hormone progesterone (P4), acting via the nuclear P4 receptors (PRs) in decidual stromal cells (DSCs) is essential for pregnancy maintenance, and loss of P4/PR signaling induces parturition. Inflammation at the chorion-decidua interface (CDI) triggers term and preterm parturition; however, the mechanism is uncertain. This study tested the hypothesis that pro-labor inflammatory stimuli induce parturition by increasing expression of the P4-metabolizing enzyme, aldo-keto reductase 1C1 (AKR1C1), which converts P4 to an inactive form, thus causing localized intracellular loss of P4/PR signaling. Here, we utilized human CDI tissue, a decidual stromal cell line, and Rhesus macaque and mouse models of preterm birth to determine that 1) AKR1C1 is induced by inflammation and metabolizes P4 thereby starving the receptor to induce a local P4 withdrawal, which can be prevented with an AKR1C1 inhibitor BPSA and 2) Inflammation-induced AKR1C1 transcription is dependent on MAPK and NF-kB signaling. Taken together, our data support the hypothesis that inflammatory stress promotes labor by inducing AKR1C1-mediated P4 withdrawal in DSCs. Importantly, our data suggest that risk for inflammation-induced preterm birth could be reduced by targeting AKR1C1 activity in uterine P4 target cells. This can be achieved via inhibition of AKR1C1 activity (e.g., with BPSA), by preservation of PR activity by treatment with a P4 analog that is not metabolized by AKR1C1 (e.g., R5020), and/or by inhibition of IL-1β-induced AKR1C1 expression in DSCs (e.g., by treatment with an IL1 receptor antagonist such as Anakinra). Furthermore, P38 inhibition may be a viable therapeutic strategy to prevent induction of AKR1C1 transcription.

Doctor of Philosophy, The Ohio State University, 2024, Nursing

Background: Diabetes is an independent risk factor for cognitive impairment and dementia. Social isolation and loneliness are modifiable yet understudied factors that may exacerbate the effect of diabetes on cognitive impairment. Furthermore, evidence of physiological mediators (systemic inflammation and sleep disturbance) in the relationship between social isolation, loneliness, and cognitive function is limited, highlighting the need for further research. Purpose: The aims of this study were 1) to examine the effects of social isolation and loneliness on the initial levels of cognitive function and rates of cognitive decline in older adults with diabetes, 2) to investigate the mediating effect of systemic inflammation on the longitudinal association between social isolation and cognitive function, and 3) to determine the mediating effects of physiological mediators on the associations between social isolation, loneliness, cognitive function, and to identify whether these association vary by the presence of diabetes. Methods: A secondary analysis of existing data from the University of Michigan Health and Retirement Study (HRS) was conducted. Data from participants aged 50 and over with diabetes were analyzed. This study utilized data from the Steptoe Social Isolation Index, the UCLA loneliness scale, C reactive protein results, and the Jenkins Sleep Scale to measure social isolation, loneliness, systemic inflammation, and sleep disturbances, respectively. Cognitive status was measured using data from the telephone interview. Latent growth modeling, a cross lagged panel model, and multigroup analysis within a structural equation modeling framework were used. Results: For Aim 1, social isolation and loneliness negatively affected the initial levels of cognitive function, but were not associated with a faster decline in cognitive function in older adults with diabetes over the ten year timeframe. For Aim 2, this study found reciprocal negative longitudinal (open full item for complete abstract)

Doctor of Philosophy, Case Western Reserve University, 2024, Chemistry

Free radical-induced oxidation of lipids generates a vast array of molecules. One of these is a phospholipid ester of 8-oxo-4-hydroxyoct-2-enoic acid. A chemical mechanistic hypothesis suggested that conjugation of this a,b-unsaturated aldehyde with glutathione could lead to the formation of a molecule, which we named pseudo leukotriene (øLT)C, that bears structural and functional resemblance to leukotriene LTC4. Catabolism of LTC4 to a glycyl cysteine derivative LTD4 and of LTD4 to a cysteine derivative LTE4, suggested that øLTC would be catabolized to produce a glycyl cysteine derivative øLTD and then a cysteine derivative øLTE. Because LTE4 is acetylated in the kidneys and excreted in urine, the production of N-acetyl-øLTE in vivo was also postulated. To test these hypotheses, total syntheses of øLTs and N-acetyl-øLTE were performed. In ten steps, a divergent strategy generated each øLT from a single precursor, ethyl glutaryl chloride. Because two diastereomers were expected to be generated in the Michael addition of a thiol and the reduction of a ketone, each synthesis is expected to produce four enantiomers. Pure samples are especially important for testing the biological activities of øLTs. Therefore, HPLC methodology was developed that provided pure samples, as diastereomeric mixtures, of all synthetic øLTs. The ethyl ester intermediates øLTE-OEt could be separated into two pure diastereomers and a mixture of two other diastereomers, confirming that the syntheses are non-diastereoselective. Heavy isotope derivatives were also prepared and used to develop LC-MS/MS analyses to facilitate the detection, structural characterization, and quantitation of øLTs in vitro and in vivo. The Salomon group exploited these HPLC pure samples of øLTs to determine their production and biological activities in vitro and in vivo. In a pilot model study of Alzheimer's disease, I demonstrated that exposure of differentiated human neuronal SH-SY-5Y cells to the Ab1-42 peptid (open full item for complete abstract)

Doctor of Philosophy, The Ohio State University, 2024, Neuroscience Graduate Studies Program

Patients with breast cancer experience debilitating behavioral side effects and exhibit elevated concentrations of circulating inflammatory mediators, even prior to treatment. Inflammation is a proposed mechanism underlying the etiology of cognitive and mood disturbances and thus may be contributing to tumor-induced behavioral side effects. Preclinical rodent models likewise display impairments in learning/memory and anxiety- and depressive-like behaviors. In addition to tumor-induced elevations of circulating inflammatory mediators, tumor-bearing rodent models display neuroinflammation in brain regions important in regulating behavior. However, the cellular and molecular mechanisms by which tumor-induced behavioral side effects occur remain unknown. Estrogen is not only implicated in the etiology of breast cancer, but also in regulating inflammation and behavior; therefore, estrogen signaling may mediate the relationships between tumor-induced neuroinflammation and behavioral side effects. Here, I examine the extent to which 1. estrogen modulates tumor-induced neuroinflammatory and behavioral outcomes and 2. different cells in the brain (i.e., microglia and endothelial cells) contribute to the observed tumor-induced neuroinflammatory phenotype using orthotopic and syngeneic mammary tumors in female mice. In Chapter 2, I demonstrate that ovarian status modulates tumor-induced endocrine and neuroinflammatory outcomes. Most notably, I show that a mammary tumor in ovary-intact mice reduces circulating estradiol and alters estrogen-related signaling in the brain. Further, tumors in ovariectomized mice increase circulating estradiol and modestly exacerbate tumor-induced peripheral and central inflammation. Next, in Chapter 3 I demonstrate that brain-specific estradiol supplementation attenuates tumor-induced fatigue in group-housed mice, but not singly housed mice; the attenuation of tumor-induced fatigue in group-housed mice is not mediated by neuroinflammatory mediato (open full item for complete abstract)

Doctor of Philosophy, The Ohio State University, 2024, Neuroscience Graduate Studies Program

Chronic stress is associated with the development of psychiatric disorders, including anxiety and post-traumatic stress disorder (PTSD). Inflammation is a key component of chronic stress and the development of psychiatric disorders. Repeated social defeat (RSD) is a rodent model of chronic stress that induces neuronal activation, microglial reactivity, and monocyte accumulation. RSD is associated with the development of anxiety-like behavior, social and cognitive deficits, and enhanced fear memory. RSD is clinically relevant as it shares key cellular and behavioral features with PTSD. Microglia play a key role in facilitating monocyte accumulation and anxiety-like behavior following RSD. Additionally, microglia have a primed profile 24d after the cessation of RSD, but how microglia mediate social and cognitive deficits or how microglia communicate with other cells after RSD is unknown. Therefore, single-cell(sc)RNAseq and single-nuclei(sn)RNAseq of the hippocampus was done 14h after RSD (Chapter 2). Here, novel stress-associated microglia were identified and uniquely characterized by cytokine/chemokine, EIF2, and phagocytotic signaling. Microglia depletion with PLX5622 (CSF1R inhibitor) prevented RSD-induced transcriptional changes to endothelia and astrocytes, but had limited, yet regionally specific effects on neurons. Furthermore, RSD-induced social withdrawal and cognitive impairment were microglia dependent. Collectively, these stress-associated microglia influenced transcriptional profiles in the hippocampus linked to social and cognitive deficits. RSD also induces stress-sensitization, where mice have amplified neuronal, immune, and behavioral responses to acute stress 24d later. The mechanisms underlying stress-sensitization are unclear. Thus, the next step of this study was to determine the influence of microglia and neuronal IL-1R1 (nIL-1R1) in stress-sensitization and fear memory after RSD (Chapter 3). Here, RSD enhanced fear memory acutely. Importantly, (open full item for complete abstract)

Doctor of Philosophy, Case Western Reserve University, 2024, Pathology

Activation of Toll-like Receptors (TLRs) induces inflammation regulated by members of the nuclear factor kappaB (NF-κB) transcription factor family. NF-κB c-Rel, a subunit of NF-κB, is a key regulator of inflammatory signaling, and is critical in specific dendritic cell functions. Dendritic cells bridge the innate and adaptive immune response through the secretion of cytokines, sampling and presentation of antigens, and activation of naive T cells during immune response. In this work, we describe the role of c-Rel following TLR activation as an important regulator of dendritic cell function. We describe the TLR7/c-Rel signaling axis and its critical role in the expression of inflammatory cytokines needed for psoriasis pathogenesis. We found that TLR7 agonism, and not application of its vehicle compound isostearic acid, is the primary driver of the Aldara-induced psoriasis mouse model, thus elucidating important mechanisms behind disease models. Finally, we describe how the increase in O-GlcNAcylation, and the enhancement of c-Rel specific O-GlcNAcylation, during TLR4 signaling regulates dendritic cell activation. Together, this work expands on the fundamental understanding behind how c-Rel acts as a transcriptional regulator during TLR signaling, and the downstream consequences in disease propagation.

Doctor of Philosophy, The Ohio State University, 2024, Psychology

Background: Approximately one-third of depression cases feature clinically elevated inflammation. The Social Signal Transduction Theory of Depression outlines one pathway to inflammation-driven depressive symptoms. It posits that those who report more frequent social stress and who have heightened inflammatory responses to an acute laboratory social stressor will have the greatest depressive symptom increases over time. Aims: This series of studies tested the Social Signal Transduction Theory of Depression, and whether this pathway is specific to social stress. It also investigated whether omega-3 supplementation impedes this etiological pathway, especially among those who are socially stressed. Methods: To test the Social Signal Transduction Theory of Depression, 76 physically healthy adults and 79 breast cancer survivors completed a laboratory social stressor (a marital conflict or the Trier Social Stress Test, respectively), had their blood drawn to assess inflammatory responsivity, and reported their stress exposure at baseline and their depressive symptoms at baseline and follow-up (one month later or four and eight months later, respectively). To test omega-3's effect on inflammatory responses, 138 middle-aged, sedentary adults were randomized to 2.5 g/day of omega-3, 1.25 g/day of omega-3, or placebo for four months. Before and after supplementation, they completed the Trier Social Stress Test and repeatedly had their blood drawn to assess inflammatory responsivity. The final study features secondary analyses from the same randomized, controlled trial to examine whether omega-3 reduced self-reported depressive symptoms among those who reported more social stress. Results: In the first study, those who reported more frequent social stress, but not other types of stress, and had greater inflammatory responsivity at baseline had heightened depressive symptoms at follow-up. This effect was specific to social stress. In the second study, omega-3 iii supplemen (open full item for complete abstract)

Master of Science, The Ohio State University, 2024, Human Ecology: Human Nutrition

Current dietary guidelines recommend the consumption of 3-4 ounces of whole grains per day. However, evidence from controlled trials is equivocal whether meeting recommendations effectively manages cardiometabolic risk, especially glucose intolerance. Understanding the benefits of whole grains is important consistent with prediabetes afflicting 38% of US adults, which drives their risk for overt type 2 diabetes mellitus (T2DM) and premature mortality. The objective of this thesis was to investigate whole wheat-mediated changes in glucose tolerance, insulin, and inflammation in persons with and without a family history of diabetes (FHD). The hypothesis was that whole grain consumption would improve glucose tolerance and inflammation in persons with prediabetes, and that the effect would be greater in persons with no FHD. To test this, a randomized, controlled, crossover trial was conducted in persons with unmanaged prediabetes in which they received a fully prescribed eucaloric diet containing white bread (WHITE) or wheat bread (WHEAT; 4 daily slices) for 2 weeks. Plasma glucose, insulin, C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) were measured prior to and after each 2-week study arm. Postprandial glycemia and insulinemia were also assessed following an oral glucose tolerance test at the end of each study arm. Participants (n = 39) completed the trial with high-compliance to test bread consumption (99.7%) and adherence to the controlled diet (97.5% of prescribed iii diet) regardless of treatment arm. Fasting glucose and insulin were unaffected by WHEAT. However, postprandial glucose was lower (P = 0.03) and postprandial insulin tended to be higher (P = 0.06) in WHEAT. Only those with no FHD were observed to have improved glucose tolerance (P = 0.004) and a tendency for higher postprandial insulin (P = 0.10). Although insulinogenic index (IGI) and disposition index (DI) scores were unaffected by WHEAT in all participants (open full item for complete abstract)

Doctor of Philosophy, The Ohio State University, 2024, Biomedical Sciences

Cancer patients experience debilitating physiological (e.g., gastrointestinal) and behavioral (e.g., cognitive decline) symptoms due to the cancer itself and subsequent cancer treatments. These symptoms are related to reduced quality of life and treatment delays and dose reductions, thereby increasing patient mortality. Inflammation and gut microbiome disruptions are both commonly hypothesized to play a role in these symptoms. Here, I investigate the extent to which breast cancer and chemotherapy independently and synergistically cause immune dysfunction, gut microbiome disruption, and physiological and behavioral symptoms. Chapter 2 characterizes a comprehensive breast cancer mouse model in terms of immune, neuroimaging, and behavioral effects. In this model, chemotherapy induced inflammation, neuroimaging alterations, and reduced locomotor activity. In chapter 3, I demonstrate that mammary tumors blunt microglial and behavioral responses to immune challenges in mice. This impairment of immune and behavioral responses is specific to a peripheral route of immune challenge administration, suggesting a non-brain-specific mechanism. Chapter 4 demonstrates that chemotherapy induces gut microbiome disruption, elevates circulating TNF-α, and induces cognitive decline in breast cancer patients. Furthermore, cognitive decline is related to decreases in microbial diversity but not elevated circulating cytokines. Finally, in chapter 5, I show that decreased gut microbial diversity prior to chemotherapy treatment predisposes breast cancer patients to chemotherapy-induced gut microbiome disruption and gastrointestinal symptoms. The findings of this work demonstrate that tumors lead to immune dysfunction and behavioral consequences in a preclinical model of breast cancer. Furthermore, this work delineates the roles of chemotherapy-induced gut microbiome disruption and inflammation in the development of cognitive decline and gastrointestinal symptoms in a population of breast can (open full item for complete abstract)

Doctor of Philosophy, The Ohio State University, 2024, Human Ecology: Human Nutrition

Chemotherapy is a common cancer treatment that induces neuroinflammation and may contribute to cancer-related cognitive impairment (CRCI). A higher intake of Omega-3 polyunsaturated unsaturated fatty acids (PUFAs) may reduce inflammation. In our previous mouse model of chemotherapy, Eicosapentaenoic acid (EPA) and Docosahexaenoic Acid (DHA)-enriched diets were shown to reduce pro-inflammatory biomarkers in the cortex, including Interleukin-6 (IL-6) and Keratinocyte chemoattractant / growth-regulated oncogene (KC/GRO) in the context of a background diet low in fat (19% of kilocalories). Considering that the majority of breast cancer survivors are overweight or obese at the time of diagnosis and high-fat diets can promote the develoment of obesity, EPA and DHA in diets with different fat contents should be evaluated to determine effects on neuroinflammation and neurodegeneration. In addition, the association of blood levels of fatty acids with cognitive function and the underlying mechanisms of CRCI have not been well studied in breast cancer survivors. In addition to omega-3 PUFAs, omega-6 PUFAs are also important for inflammatory processes. Moreover, we have found omega-9 monounsaturated fatty acids (MUFAs) to rise in mice brain after chemotherapy treatment, potentially suggesting neurodegeneration. Therefore, this dissertation will focus on understanding the relationship of fatty acids in the diet and blood, including omega-3 and omega-6 PUFAs and omega-9 MUFAs, with neuroinflammation, neurodegeneration, and cognitive outcomes in a chemotherapy-treated mouse model and human breast cancer survivors. The first project of this dissertation evaluated whether a diet rich in long-chain omega-3 fatty acids, eicosapentaenoic acid, and docosahexaenoic acid (EPA and DHA) could reduce neuroinflammation and neurodegeneration in a mouse model of chemotherapy. In this study, female C57BL/6 mice were randomized to high fat, high fat omega-3, or low-fat diet groups for 8 week (open full item for complete abstract)

Doctor of Philosophy, The Ohio State University, 2024, Biomedical Sciences

The innate immune response to infection involves a complex series of signaling events, threat recognition molecules, and effector proteins that act together to eliminate pathogens. As part of the patrolling immune cells, monocytes are often the first responders to infection and are specifically equipped to recognize a diverse range of pathogens and quickly respond to threats. One of these mechanisms involves a series of proteins known as inflammasomes that are critical for producing an adequate immune response to fend off pathogen infection while simultaneously being regulated to prevent hyper inflammation and inflammatory diseases such as sepsis. Inflammasomes are multimeric complexes that become activated upon pathogen detection by an upstream sensor molecule that can be in response to both bacterial and viral infection. Once activated, a highly regulated signaling cascade occurs that results in the eventual enzymatic activation of the pore forming protein Gasdermin D (GSDMD). Once activated, GSDMD traffics to cellular membranes to form pores often leading to an inflammatory form of cell death known as pyroptosis. While cell death is necessary to maintain homeostasis and cell turnover, dysregulated cell death in the case of GSDMD induced pyroptosis can lead to severe inflammatory diseases such as sepsis and acute respiratory distress syndrome (ARDS). Despite significant advances in unraveling the mechanism of GSDMD activation and designing targeted therapeutics against inflammation, gaps in knowledge still persist as evident by the high mortality rate of sepsis and inflammatory disorders. As such, it is essential to improve our understanding about the signaling events leading to GSDMD activation, the impact of active GSDMD on inflammation and cell death, and the regulators involved with GSDMD activation. Our lab has recently discovered a novel avenue of GSDMD mediated cell injury through the release of monocyte derived exosomes (EVs) containing active GSDMD that a (open full item for complete abstract)

Doctor of Philosophy, The Ohio State University, 2024, Psychology

Perceived discrimination is a psychosocial stressor defined as the experience of unfair treatment based on race, sex, religion, or other characteristics. Experiences of discrimination have been associated with negative physical and psychological health outcomes. Though less frequently studied, discrimination has also been linked to adverse cognitive outcomes. Discrimination is particularly important to study as chronic stress may accelerate preexisting vulnerabilities, thereby exacerbating negative health outcomes. The goal of this project is to clarify the role of discrimination in two important contexts: racial disparities in cognitive health and age-related cognitive decline. The current study will examine the association between discriminatory experiences and cognitive functioning in a sample of healthy adults from the Midlife in the United States (MIDUS) dataset. Moreover, I will leverage the comprehensive biological and psychological information available through MIDUS to explore the mediating impact of inflammatory markers, metabolic syndrome, and allostatic load, as well as the moderating impact of psychosocial factors on these relationships. I will test these relationships by pursuing three specific studies. Study 1 investigates whether perceived discrimination mediates the relationship between self-reported race and cognitive functioning. Study 2 describes the relationship between perceived discrimination and cognition across the lifespan. Additionally, this study will explore the role of moderating social factors on the relationship between discrimination and cognition. Study 3 then clarifies the role of health mediators in these relationships. The implications of these results are threefold. First, they will provide a more comprehensive understanding of the relationship among these factors; second, they will highlight who may be at increased risk for cognitive decline following experiences of discrimination; and third, these results may enable researcher (open full item for complete abstract)

Doctor of Philosophy, The Ohio State University, 2023, Neuroscience Graduate Studies Program

Sensorineural hearing loss (SNHL) is a common hearing health disorder caused by damage to cochlear sensory hair cells and neurons, which can occur during normal aging and from acoustic insults throughout the lifespan. Age-related hearing loss (ARHL) describes the form of SNHL that happens in aging patients with progressive loss of hearing perception. Noise-induced hearing loss (NIHL) occurs from noise damage and can happen at any age. Both ARHL and NIHL share similar features in cochlear tissue damages, including the loss of sensory hair cells, auditory neurons, and synapses in the cochlea. Further synaptopathy occurs in the cochlear nucleus (CN), which is where all arriving auditory information from the ear first enters the central nervous system. Acute and chronic cochlear inflammation are associated with worsening outcomes in SNHL. Resident innate immune cells modulate local inflammatory responses and are implicated in both the cochlea and the brain during SNHL. Tissue damage and age-related degeneration increase the activation of both cochlear macrophages and microglia in the brain. These activated immune cells release factors that recruit additional immune cells and alter tissues in ways that can contribute to the progression of pathology. Example signals potentially released by resident immune cells include complement factors, which are proteins also found in circulation that can accumulate in damaged or diseased tissues. This dissertation investigates the activation of innate immune cells, including cochlear macrophages and microglia during ARHL and NIHL, and whether the activation of complement pathways in the cochlea and CN may contribute to SNHL pathophysiology. CBA/CaJ mice were used as the animal model in this research, which were either aged in ambient noise environments to develop ARHL or exposed to various intensities of noise to cause NIHL. Hearing was assessed in all mice and tissues were collected to measure changes in the resident immune cells and (open full item for complete abstract)