Master of Science (MS), Wright State University, 2024, Biochemistry and Molecular Biology

Duchenne Muscular Dystrophy (DMD) is a devastating progressive muscular disorder caused by a mutation in the dystrophin gene affecting approximately 1 in 3,500 males. However, despite its prevalence, there is currently no cure for this disease. Mutations in dystrophin lead to enhanced inflammation, fibrosis, cell death, development, and decreased skeletal muscle function. Phosphatidylcholine, synthesized by choline, is a major phospholipid that functions in maintaining and synthesizing cell membranes and has previously been found to be decreased in DMD patients. This led us to hypothesize that the dystrophic phenotype could be improved through treatment with choline. In this study, we used concentrated choline to treat B10 wildtype and mdx mice for both short-term and long-term treatments. We found that compared to untreated groups, treatment with choline showed less inflammation, fewer macrophage markers, and reduced fibrosis development within the skeletal and cardiac tissue of mdx mice. We also found that within skeletal muscle, necroptotic protein markers were downregulated as a result of choline treatment. We further evaluated the effects of choline treatment on dystrophic skeletal and cardiac muscle function to explore the potential mechanism of action. This study determined whether choline could be a potential therapeutic agent for the treatment of DMD.

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

Across three articles, this dissertation analyzes patterns of dental defect formation and childhood physiological stress within the population of Neolithic Catalhoyuk (ca. 7100-5950 BCE), in order to contribute to a better understanding of biological, temporal, and social variation within this important early “megasite” community. Article one addresses biological questions with important methodological implications regarding the impact of linear enamel hypoplasia (LEH) defects on inter- and intra-population variability in relationships between incremental enamel microstructures. Relationships between perikymata (PK) periodicity and distribution were tested from high-definition epoxy replicas and histological thin-sections of unworn mandibular canines (n = 15) with high LEH prevalence from Catalhoyuk. Findings re-affirm the existence of significant inter-population variability and suggest that high LEH prevalence likely increases PK distribution variability and weakens relationships with periodicity. PK distribution-based methods may nevertheless help narrow likely periodicity ranges and improve microstructure-based chronological age estimation accuracy even in highly LEH-impacted samples. To better understand relationships between population aggregation and physiological stress in early human settlements, Article two tests whether LEH prevalence or timing change significantly over time alongside population levels at Neolithic Catalhoyuk. LEH defect frequency scores (n = 109), defect-per-individual (DPI, n = 44), and defect initiation age (DIA, n = 44) were collected from epoxy canine replicas. LEH measures did not differ significantly by sex or age-at-death, nor did they significantly change over time in parallel with population size. Developmental stress episodes were very common (DPI: all defects M = 11, pronounced defects M = 6; DIA: all defect M = 3.9 years, pronounced defects M = 4.0 years), with 100% of observable individuals experiencing at least one de (open full item for complete abstract)

PHD, Kent State University, 2023, College of Arts and Sciences / School of Biomedical Sciences

The cetacean transition from life on land to an exclusively aquatic niche is accompanied by a suite of morphological and skeletal changes that are well-documented in the fossil record and during embryonic development. The forelimb of early cetaceans transitioned from a weight-bearing pentadactyl limb to a flipper used for steering and control during locomotion. The formation of the cetacean flipper includes the maintenance of interdigital webbing between the digits and an increase in the number of phalanges on some fingers and reduction of phalanges on other digits. The hindlimbs, initially robust appendages that powered amphibious fossil cetacean taxa, are greatly reduced to internalized vestiges in modern animals. Reduction of the hindlimbs occurred concurrently with morphological homogenization of the post-thoracic spine and the de-novo evolution of the soft-tissue flukes. The flukes insert onto the spine at the terminal caudal vertebrae and are used to propagate forces during tail driven locomotion. These three major transitions in skeletal morphology, the formation of the flippers, reduction of hindlimbs, and evolution of the flukes, all occurred within the span of approximately 8 million years during the Eocene and have been retained in modern taxa. The goal of this dissertation is to investigate key aspects of cetacean appendage evolution and development, specifically those related to this shift from limb-powered to tail-powered locomotion.

Bachelor of Science (BS), Ohio University, 2023, Biological Sciences

Properties of the avian skeleton system such as histological organization and cross-sectional geometry have been used to make inferences about organismal biology, locomotion, ecology, and evolution. However, we lack a fundamental organization about how bone naturally develops. This study is the first of its kind, examining developments in vascular orientation, shape, and post-cranial pneumatization in a controlled turkey model. The use of such a model allows for the observation of natural bone development in the absence of ecological or locomotive factors. The humerus and ulna were examined using both micro-CT and a histological workflow. Our results indicate certain periods (weeks 5-7) characterized by notable increase in length and cross-sectional shape measured used to infer resistance to mechanical loading. There is also variation in cortical area (thickness) that may be due to redistribution of cortical bone around the neutral axis. Circumferential canals appear at the border of developing bone and later in the growth series, suggesting it is a normal part of bone development. However, regional differences in histological organization paint a complicated picture between canal orientation and factors such as growth or locomotion. Post-cranial pneumatization of the midshaft appears at week 4 in humeri and air-like space is found in the ulna, which has previously been interpreted as a non-pneumatic bone. This project lays a foundation for further studies into bone as a developing system, helping to understand how bone's appearance may be related to its environment, ecology, growth, and locomotion.

Master of Science, The Ohio State University, 2023, Comparative Biomedical Sciences

Mitosis is a critical biomarker for numerous cancers, including soft tissue leiomyosarcoma. Despite the ubiquity and importance of mitosis detection in tumor histopathology sections, there has been little investigation into whether cell organization within a mitosis detection region can elicit high interpathologist reproducibility and high mitotic count. In vitro, smooth muscle cells form bundles with parallel cell alignment, and the mitotic axes of dividing cells align with the longitudinal axes of these bundles. We hypothesized that this phenomenon would be conserved in histopathology sections of spindle-pattern soft tissue leiomyosarcoma and that, in turn, interpathologist agreement and mitosis detection density would be increased in regions of longitudinal cell orientation with respect to plane of section. Three resident pathologists annotated mitotic figures and cell orientation with respect to plane of section (longitudinal or transverse) in three mitosis counting regions of 30 whole slide images of spindle-pattern soft tissue leiomyosarcoma. We found that regions of longitudinal cell orientation had both higher interpathologist reproducibility and higher mitotic density than did regions of transverse cell orientation and that this disparity had a direct impact on histologic grading. The most reproducible mitotic phases were detected more often in longitudinal regions compared to transverse regions, and the least reproducible mitotic phases exhibited no detection disparity between longitudinal and transverse regions. In addition, there was alignment of metaphase, anaphase, and telophase mitotic axes with local cell axes in longitudinal but not transverse regions. Taken together, these findings suggest that regions of longitudinal cell orientation are superior to regions of transverse cell orientation for reproducible and high density mitosis detection in spindle-pattern soft tissue leiomyosarcoma. However, there was significant interpathologist disagreement in (open full item for complete abstract)

Master of Science, University of Akron, 2022, Biology

Species identification of skeletal remains is a central duty in forensic anthropology. This process can be made difficult or impossible due to taphonomic changes, including burning, that lead to fragmented or distorted remains. This study employs histomorphological and histomorphometric methods, such as measuring osteon area and circularity, to determine if species differentiation is possible in skeletal remains burned at 600°C and 700°C. The right femora, ulnae, and sixth ribs were obtained from a cow, white-tailed deer, dog, human, pig, and raccoon (all species n=1) for analysis. Control groups were compared with eperimental groups burned in a controlled environment to discern skeletal histological changes due to burning. Qualitative assessments and descriptive statistics were collected and analyzed. At 600°C, histomorphological variables (eg. cement lines, osteocyte lacunae, etc.) remained visible and histmorphometry could be measured. At 700°C, only degraded endosteal cement lines and Haversian canals were present, preventing the accurate usage of histomorphometry. This study reaffirms the utility of these methods in remains burned at temperatures of up to 600°C by detecting differences in histomorphology and osteon geometry between human and nonhuman samples.

Doctor of Philosophy, University of Akron, 2022, Integrated Bioscience

Opioids have become one of the most misused classes of prescribed medication. Synthetic opioids (e.g., fentanyl) have been responsible for most opioid overdose deaths since 2017. As this epidemic shows no signs of slowing, it is imperative to study the effects of opioids on various aspects of health including bone maintenance. Endogenous opioids (e.g., met-enkephalin) are involved in osteogenesis and bone remodeling. Exogenous opioids can interfere with bone maintenance directly through binding to osteoblasts, limiting bone formation, or indirectly through a cascade of effects limiting sex hormone production. To understand how opioids affect bone microarchitectural and biomechanical properties we first examine bone microstructure throughout the human lifespan to see natural changes occurring without the effects of opioids. Using both Synchrotron Radiation micro-Computed Tomography and confocal laser microscopy, we found bone and lacunar volume fractions to decrease with advancing age while pore diameter increased in the anterior midshaft femur. After finding how bone changes with age under normal circumstances, we sought to examine how prolonged opioid administration affected trabecular microstructure in a model organism (rabbit). We used μCT to examine the proximal tibia by anatomical quadrant (e.g., anterior, posterior). We found that morphine animals had greater bone volume fraction and less trabecular separation than controls. Fentanyl animals had significantly thicker trabeculae and increased trabecular spacing than controls. Detected differences by anatomical region followed the same overall pattern, suggesting biomechanical or anatomical variation rather than due to opioids. We finally examined overall bone strength in a non-weight bearing bone (rib) of the rabbit using uniaxial compression testing to determine how opioids affect overall mechanical competency. We found no difference in mechanical variables between opioid and control groups. Only rib span leng (open full item for complete abstract)

PHD, Kent State University, 2022, College of Arts and Sciences / School of Biomedical Sciences

Having transitioned from a terrestrial lifestyle to an aquatic one over roughly 50 million years, cetaceans (whales, dolphins, and porpoises) make for prime subjects of study of respiratory and olfactory anatomy. As obligately aquatic mammals, they are often considered to have reduced olfactory anatomy. Here, I provide evidence that baleen whales have retained this anatomy, and toothed whales lack olfactory anatomy. In reconstructing the upper respiratory tracts of prenatal dolphins from computed tomography, I document the anatomy of the air sacs, pterygoid sinus systems, and asymmetries thereof. Olfactory anatomy was absent. However, in bowhead whales (Balaena mysticetus), a species of baleen whale, nasal chambers and turbinates were visible in prenatal development. I describe and clarify the anatomy within their nasal chambers. Olfactory epithelium, identified histologically, covers the dorsalmost and caudalmost corner of the nasal chamber, including some of the ethmoturbinates. I identify olfactory epithelium using explicit criteria of mammalian olfactory epithelium. Immunohistochemistry revealed the presence of olfactory marker protein, which is only found in mature olfactory sensory neurons. Although it seems that these neurons are scarce in bowhead compared to typical terrestrial mammals, our results suggest that bowheads have a functional sense of smell, which they may use to find prey. The closest living relatives of cetaceans are artiodactyls, even-toed ungulates, such as sheep, camels, and giraffes. I used Cetartiodactyla, the clade that comprises artiodactyls and cetaceans, as the taxon to test the relationships found in Bird et al. (2018). They found that once body mass and phylogeny are accounted for, it is possible to use the surface area of the cribriform plate to predict the number of olfactory receptor genes that fossil mammals have. I confirmed their results and predicted gene counts in fossil whales, thereby documenting a decrease in (open full item for complete abstract)

Master of Science, Miami University, 2022, Cell, Molecular and Structural Biology (CMSB)

The transcription factor, PAX6, plays essential roles during the development of eyes, brain, and pancreas. Loss of Pax6 causes complete lack of eye formation in both humans and mice and even prenatal lethality in mice. Heterozygotes for Pax6 null mutations possess “small eyes” in mice and aniridia in humans. Truncation mutations of human PAX6 C-terminus can also lead to aniridia, demonstrating a critical role of the PAX6 transactivation domain (TAD) during eye formation. Previous studies found that in vitro phosphorylation of the PAX6 TAD by p38 kinase and HIPK2 at seven sites could regulate Pax6 transactivation. Here, a comprehensive analysis of all thesis phosphorylation sites revealed that PAX6 lost almost all ability to activate transcription when all sites were mutated. Furthermore, phosphorylation of the last site accounts for about 40% of the transcriptional activity and plays the most dominant role among all the phosphorylation sites studied. Additionally, it was proved that TAD phosphorylation could critically regulate Pax6 transcriptional repression. Together, these in-vitro data demonstrate that PAX6 TAD phosphorylation can strongly affect the dual function of Pax6 as a trans-activator and transrepressor. Transgenic mice with sites 2 and 3 mutations exhibited normal eye development, which was consistent with the in-vitro data.

Doctor of Philosophy, Case Western Reserve University, 2022, Molecular Medicine

Inflammatory bowel disease (IBD) is a chronic disease that causes relapsing inflammation in the gastrointestinal tract. Multiple risk factors have been attributed to the onset and progression of IBD, including host genetics, environmental factors, and microbes. Epidemiological studies have linked the emergence of IBD in new populations to the initiation of industrialization, and along with it the rise in consumption of a “Western-style” diet. Food additives, an integral component of the processed foods present in the Western diet, have been implicated in aggravating inflammation in IBD in both pre-clinical models and a small subset of clinical studies. Diet is a modifiable risk factor, and therefore this study aimed to investigate patient-perceived feasibility of diet therapy and a specific target for elimination in diet protocols. First, we surveyed a population of pediatric IBD patients to determine their knowledge of their disease and its treatments, their perceptions of diet's influence on their symptoms, and their willingness to purposefully modify their diet. Dietary modification has been shown to be effective in pediatric populations, but diet is closely tied to social interactions and therefore may be undesirable to modify. Nearly 60% of subjects perceived diet as a symptom trigger, with just under half of subjects attempting a dietary modification protocol for symptom resolution. Success was limited among patients who attempted dietary modification as they often did so without physician guidance. Subjects experiencing active disease symptoms as determined by Manitoba IBD Index were more likely to be currently modifying their diet compared to subjects without active disease symptoms (odds ratio = 4.11, confidence interval = 1.58, 10.73, p = 0.003). This study determined that adolescent IBD patients perceive a link between their disease symptoms and are willing to modify their diet for relief. In our second study, we evaluated the effects of the ubiqui (open full item for complete abstract)

Doctor of Philosophy, The Ohio State University, 2021, Biomedical Sciences

Tissue engineered scaffolds and regenerative medicine-based therapeutics hold great potential for a growing patient population in need of alternative tissue replacements. The initial work of this dissertation is on efforts to improve the translational capability of tissue engineered vascular grafts (TEVGs) to the clinic. A challenge in translating our group's TEVGs, as well as is seen with other tissue engineered scaffolds, is balancing the host response where an appropriate amount of healthy neotissue is created and remodeled overtime replacing the biodegradable scaffold and avoiding complications such as graft thrombosis and stenosis. Approaches to optimize tissue engineered scaffolds for use in patients often focuses on material alterations, cell seeding, bioreactor growth, or drug/small molecule co-administration. Seeding our TEVGs with bone-marrow derived nucleated cells has proven to be an effective approach to minimize graft occlusion and alter neotissue development; however, the exact mechanism underlying this remains unclear. The initial focus of this dissertation sought to elucidate what effect interleukin-10, an anti-inflammatory cytokine, had on graft patency and neotissue development from cells seeded onto TEVGs, from the host TEVG recipient, and from a recombinant protein drug delivery. This work demonstrated interleukin-10 from the host was critical in maintaining TEVG patency. Another promising approach optimizing a thrombosis and stenosis resistant TEVG has been our group's investigations into a novel wound healing modulator known as the lysosomal trafficking (LYST) protein. The protein, encoded by the LYST gene, is poorly understood with much of existing information coming from observations into disease states and cellular dysfunction that occurs in presence of a LYST gene mutation. A notable cellular finding is the perniculear clustering of enlarged lysosomes in mutant LYST cells due to defects in lysosomal fusion/fission. We serendipitously (open full item for complete abstract)

Bachelor of Science of Journalism (BSJ), Ohio University, 2021, Journalism

American socialist publications have all grappled with the conundrum of staying financially stable within a capitalist society. This has historically resulted in two outcomes: a compromise of values to increase funding like increased advertising, exploitive labor practices and/or the courting of wealthy donors, or the publication's demise. How does modern American socialist magazine Jacobin fall into this American tradition of socialist media? How has it stayed financially stable, and how has its content changed, if at all, in its 10 years of operation? The purpose of this thesis is to analyze Jacobin's content and business practices and place it into the greater historical context of American socialist media.

Doctor of Philosophy, University of Akron, 2021, Polymer Science

Wound dressings play a pivotal role in providing favorable wound healing outcomes. Active dressings which incorporate bioactive agents such as anti-inflammatory drugs, antimicrobial compounds or peptides and proteins can help to alleviate patient pain and reduce healing times. This is especially true for diabetic ulcers, which are wounds that are stuck in the inflammatory stage of wound healing and are often associated with bacterial infection. This work describes the development of wound dressings capable of improving healing outcomes. To do so, a series of functional polyesters derived from a modular N-substituted diol monomer platform were synthesized. Wound dressings comprising these polyesters were fabricated using the 3D printing and electrospinning techniques. Dyes serving as model drug compounds were released from electrospun dressings to show the ability of these dressings to deliver drugs. The two fabrication techniques were used to create dressings comprised of varying polyester compositions. An in vivo acute wound rat model showed that despite their varying compositions and thread sizes, none of them were detrimental to normal healing processes. Electrospun dressings showed broad spectrum antimicrobial activity in an acute infected wound mouse model when an antimicrobial poly(ester urethane) was incorporated. Finally, 3D printed scaffolds were conjugated with peptides capable of recruiting keratinocytes and fibroblasts in an attempt to improve healing outcomes in an acute wound rat model. These studies seek to guide future researchers in the design and implementation of active wound dressings, especially by showing the utility of functionality within those dressing systems.

Doctor of Philosophy (PhD), Ohio University, 2020, Translational Biomedical Sciences

Emerging evidence has demonstrated that the gut microbiome plays an important role in both host physiology and pathophysiology of disease. That is, gut microbes and their metabolites influence host metabolism, endocrinology, immunology, neurology, and growth. For instance, gut microbes have been shown to impact linear growth partially by altering the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis. Conversely, several metabolic and intestinal diseases (including chronic undernutrition, inflammatory bowel disease, non-alcoholic fatty liver disease, obesity, and diabetes) not only share a lack of microbial diversity in the gut but have abnormalities in GH action. To date, however, limited research has focused on the potential impact of GH on the gut microbiome. The studies detailed in this dissertation thus aimed to investigate the potential role of GH on the gut microbial profile. The first study optimized the methodology to quantify the mouse gut microbiome from fecal collection to data analysis. The second study set out to characterize the microbial abundance, maturity, and predictive metabolic function in two mouse lines of opposing GH action: 1) a GH deficient (GH-/-) mouse line and 2) a GH excess mouse line (bGH). We observed several distinct microbial and intestinal findings in both mouse lines compared to controls. Collectively, the results presented suggest that GH indeed alters the gut microbiome. Moreover, opposing microbial trends between the two mouse lines suggest that GH is associated with the presence of certain microbes, increases maturation of the microbial community, and alters predictive metabolic pathways involved in acetate, butyrate, folate, and heme B biosynthesis. The third study delved deeper into the relationship between excess GH action and the longitudinal gut microbiome. That is, this study tracked the longitudinal changes in microbial abundance, maturity, and predictive metabolic function and intestinal phenotype in (open full item for complete abstract)

Doctor of Philosophy, The Ohio State University, 2019, Neuroscience Graduate Studies Program

Spinal cord injury (SCI) results in lasting sensory and motor dysfunction that is not completely mitigated by current treatment approaches. In order to contribute to the development of more effective treatments for individuals with SCI, the body of work presented in this dissertation sought to advance the understanding of cellular and molecular responses to injury and rehabilitation throughout the neuraxis. Chapter 2 presented a rigorous characterization of remote inflammatory responses in mice and how they evolve from acute to sub-acute stages of SCI. Here, we found that although the lumbar cord is highly vulnerable to both central and peripheral sources of inflammation early after SCI, the cervical cord remains stable throughout the acute injury response. The remarkable stability of the cervical microenvironment after SCI provided the basis for the chronic SCI investigations of rehabilitation-induced neuroplasticity, both in cervical cord and above. These findings are presented in chapters 3 and 4, where we examined the ability of a novel rehabilitation approach (downhill treadmill locomotion) to promote a novel type of neuroplasticity (white matter plasticity) in both mice and humans with chronic, incomplete SCI. In mice, we revealed that two weeks of downhill locomotor training stimulated white matter plasticity in the cervical dorsal columns rostral to the midthoracic injury. Importantly, the observed white matter plasticity in this region consisted of greater new oligodendrocytes and more numerous contacts between axons and oligodendrocyte lineage cells. Moreover, white matter plasticity was associated with rehabilitation-induced improvements in motor and sensory function. In humans with chronic SCI, myelin water imaging revealed that a 12-week downhill training regimen promoted myelin plasticity in mixed motor and sensory tracts of the ventral cervical spinal cord and in brain regions associated with motor learning. Collectively, these data reveal specificity (open full item for complete abstract)

Doctor of Philosophy, The Ohio State University, 2019, Anthropology

Rather than resisting microscopic damage, human bone tissue is adapted to disperse energy through temporary plastic deformation, which it later repairs. Under low strains, bone cells continually turn over aging bone as a stochastic maintenance operation. Under high strains, stochastic remodeling is repressed, but microscopically damaged regions are resorbed and replaced through targeted remodeling. The triggering of bone remodeling by two opposing strain environments has long confounded attempts to link bone microstructure consistently to mechanical stimuli. Additionally, bone cells become uncoupled from mechanical control as they age, and begin eroding the cortex through more extensive and unrepaired bone resorption. Intracortical porosity is often treated as a consequence of aging, when it is accumulated enough to impact bone strength and fracture risk. Yet because cortical pores are produced by both stochastic and targeted remodeling activity, they are constantly forming in all strain environments and over the lifespan. This raises the question of whether pores in high-strain environments are morphologically “optimized” or resistant to the high risk of microcrack initiation and propagation in those regions. Moreover, does porosity increase fracture risk with age not only because it is increasing porosity, but because it is reshaping it morphologically? This study fundamentally asked whether the three-dimensional geometry of pore networks is morphologically optimized to resist local mechanical strain. The hypothesis of structure-strain pore morphotypes was tested in the human right-side femoral neck, a common site of osteoporotic fracture, and the human right-side midshaft fourth rib, a relatively unloaded control, for one male and one female per age decade from 20s to 80s. Extracted regions of each bone are visualized with high-resolution micro-CT imaging to reconstruct complete three-dimensional pore networks from 10 mm thick cross-sections of bone. These ima (open full item for complete abstract)

Doctor of Philosophy (Ph.D.), Bowling Green State University, 2019, Psychology

Despite decades of neurocognitive aging research in mammals, it was not until recently that studies of neurocognitive aging in birds surfaced. Indeed, it was not until 2014 that the first reports of age-related, spatial-cognitive deficits in homing pigeons were published. It was first hypothesized that the observed cognitive deficits resulted, in part, from hippocampal formation (HF) degeneration similar to that seen in mammals. However, multiple reports have since found the HF of older, memory-impaired pigeons to be larger and contain more neurons than the HF of younger, non-impaired pigeons. As an alternative explanation for the declining spatial-cognitive ability of birds, it was hypothesized in the current dissertation that activation of the old HF would be reduced during learning of a spatial-cognitive task. To test this hypothesis, HF activation (measured via expression of the activity-dependent immediate early gene, c-Fos) in response to a spatial working memory challenge was compared between younger and older pigeons. Additionally, the effects of age on activation of the septum and nucleus of the diagonal band (NDB), which are believed to influence HF functioning, and on the number of cholinergic neurons in these regions was examined. Highlighting the important findings include: compared to younger pigeons, older pigeons had (i) decreased HF and septum neuronal activation during spatial learning, (ii) fewer cholinergic (i.e., ChAT-expressing) neurons in the septum, (iii) a stronger correlation between the number of cholinergic septal neurons and HF neuronal activity, and (iv) weaker correlated neuronal activity between NDB and HF. In summary, the data support the hypothesis that activation of the old HF would be reduced during learning of a spatial-cognitive task, as well as identifies neural correlates (functional/activational and neurochemical) of age-related, spatial-cognitive decline in pigeons in other, HF-connected regions.

Doctor of Philosophy, The Ohio State University, 2018, Anatomy

Obstructive nephropathy (ON) is the leading cause of pediatric chronic kidney disease (CKD) affecting more than 19 million people nationwide. Children affected with CKD suffer poor quality of life, often undergoing dialysis only to reach end stage renal disease (ESRD). Despite surgical advances to relieve obstruction, some patients may still advance to CKD[1]. Studies in the McHugh lab suggest that the renal urothelium is critical in the initiation and progression of CKD following the development of obstruction [2]. Even so, little is currently known regarding the development of the renal urothelium and how it specifically responds to ON [3]. The objective of this study is to gain a better understanding of the cellular lineages associated with normal kidney development and renal pathogenesis. To this end, I propose to characterize normal renal urothelial cell development and compare these results to the pathogenic response of renal urothelial cells in a disease model of ON, ureteropelvic junction obstruction (UPJO) via a surgical model called unilateral ureteral obstruction (UUO). I hypothesize that changes in proliferation rate and cell fate among specific cell populations within the renal urothelium will occur in response to UUO. These changes may be indicative of the early onset of ON and may be useful as prognostic markers of ON permitting early detection and therapeutic intervention before progression to ESRD.

Doctor of Philosophy, The Ohio State University, 2018, Comparative and Veterinary Medicine

Endometrial carcinomas arise from the epithelium of the uterine glands and are the most common gynecological malignancy. There are two major clinical subtypes of endometrial carcinomas, which present with distinct epidemiological, histological and molecular associations. Type I endometrial carcinomas account for nearly 80% of cases and are associated with a more favorable prognosis. Epidemiologically, affected women are middle-aged and peri-menopausal. Increased estrogen signaling appears to be involved in the pathogenesis of type I tumors because risk factors include estrogen supplementation, late menopause, history of tamoxifen treatment for breast cancer, obesity and polycystic ovarian disease. Histologically, these tumors arise from a background of endometrial hyperplasia and neoplastic cells are well-differentiated. PTEN mutations or loss of expression occur in 80% of type I tumors. In contrast, type II carcinomas are associated with poor clinical outcome and affected women are post-menopausal. Histologically, type II tumors arise from an atrophic endometrium and the neoplastic cells are poorly differentiated with significant nuclear atypia. TP53 mutations occur in 90% of type II tumors. Using mouse models, we attempt to further our understanding of the pathogenesis of endometrial carcinoma. We show that genetic ablation of the Pten locus is sufficient to drive malignant transformation of the uterine epithelium and a proportion of affected mice develop invasive and metastatic disease. Importantly, these tumors are phenotypically similar to type I “endometrioid” carcinomas observed in women and we propose that these mice may serve as an important preclinical model for studying the pathogenesis of type I endometrial carcinoma or novel therapies for its prevention and treatment. Interestingly, genetic ablation of the Trp53 locus does not transform uterine epithelium within the timeframes of our study indicating that there are other factors necessary to drive type (open full item for complete abstract)

Master of Sciences, Case Western Reserve University, 2018, Pathology

Immunohistochemistry (IHC) is a technique that has been used for over 70 years to detect and visualize proteins in tissues through the binding of antibodies. The technique has evolved in recent years due to numerous technical developments leading to expanded applications in clinical practice. It has become an important ancillary tool in the clinical pathology lab to support the study and diagnosis of many types of cancer. Although IHC is a powerful research and diagnostic technique, it has certain limitations, including lack of objective analysis and standardization. However, automation, multiplexing, and digital imaging technologies offer hope for overcoming some of IHC's inherent weaknesses. Immunohistochemistry can be used to identify prognostic and predictive biomarkers. Biomarker discovery is extremely important in tailoring specific treatment strategies to individual patients. Identifying chemotherapeutic targets and developing personalized medicine has emerged as an effective way to improve patient care and clinical outcome.