PhD, University of Cincinnati, 2018, Medicine: Pathobiology and Molecular Medicine

Recent technological advances in biomedical, genomics, and computational fields have brought exponential growth in both the amount and accessibility of biological data. These include health records, medical imaging data, omics data including genomics, proteomics, metabolomics, phenomics, disease, and small molecule data. The resultant biological big data poses both great opportunities and challenges. For example, the large amount of heterogeneous data not only allows researchers to query and pursue investigations in health and disease from an unprecedented wide perspective but also enables novel discoveries that were previously obscured by the lack of comprehensive and in-depth analysis. In this dissertation, I use various data-driven approaches to generate testable hypotheses and actionable biological insights related to lung development, disease, and candidate therapeutic discovery. In the first part of this thesis, I used unsupervised machine learning to identify novel cell type and sub types in developing mouse lung from embryonic day (E) 16 to post-natal day (PND) 28 and discovered functionally distinct gene modules associated with each cell populations. These gene modules are analyzed further to identify their roles in lung development, specifically, how they contribute to cell-cell communication during lung development. In the second part of the thesis, I focus on a lethal rare lung disease, idiopathic pulmonary fibrosis (IPF), and identify molecular signatures that not only explain the heterogeneous nature of IPF but also the potential molecular basis of disease severity. I analyzed a large cohort of IPF data and identified clinically significant subgroups using only transcriptomic data. Lastly, I combined connectivity mapping and systems biology-based approaches to identify and prioritize candidate therapeutics for another rare lung disorder – cystic fibrosis (CF). We identified PP-2, a src-kinase inhibitor as a novel CFTR modulator that could potentially (open full item for complete abstract)

Committee: Bruce Aronow Ph.D. (Committee Chair); Anil Jegga (Committee Member); Harinder Singh (Committee Member); Jeffrey Whitsett M.D. (Committee Member); Kathryn WiWikenheiser-Brokamp M.D., Ph.D. (Committee Member) Subjects: Bioinformatics

Master of Sciences, Case Western Reserve University, 2014, Genetic Counseling

Previous studies have identified a positive correlation between weight and pulmonary function of patients with cystic fibrosis (CF). As decreased weight in patients with CF has been observed at birth, this study aimed to identify the predictive quality of birth weight on later complications of CF. Results showed that males with CF (n=40) were on average 10.25 oz lighter at birth (p<0.01) and females with CF (n=39) were on average 9.04 oz lighter at birth (p=0.01) than national averages, matched for gender. Birth weight was correlated with FEV1% at age 6 (p=0.04) but not at ages 10, 15 and 20. Birth weight was not predictive of percent ideal body weight, the age of Pseudomonas colonization, or the incidence of cystic fibrosis related diabetes. These findings suggest that birth weight is predictive of early FEV1%; however, in older patients, other variables contribute to the majority of CF related complications.

Committee: Rebecca Darrah PhD (Committee Chair); Craig Hodges PhD (Committee Member); Anne Matthews PhD (Committee Member) Subjects: Genetics

PhD, University of Cincinnati, 2024, Medicine: Systems Biology and Physiology

Background and significance: Cystic fibrosis (CF) is a genetic disease caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CF pulmonary disease is often characterized by alveolar mucus plugging, fibrosis, chronic inflammation, progressive destruction of the structural airways, and poor ventilation. In fact, the main cause of mortality in CF remains respiratory failure, and as such, CF studies have historically focused on pulmonary outcomes. Studies report pulmonary vascular perturbations and perfusion deficits in CF patients as young as one year old. Mucus plugging and bronchial wall abnormalities only marginally explain the observed perfusion deficit. Although CFTR is expressed and functional in endothelial cells (ECs), the mechanism of pulmonary vascular disease in CF remains unknown. When endothelial cells do not function properly, reduced gas exchange between the alveoli and the pulmonary capillaries can occur, which may cause hypoxemia in CF patients. Therefore, it becomes crucial to uncover the role of CFTR in the endothelium. Objectives: The dissertation aims to investigate how CFTR dysfunction affects endothelial cell response to shear stress and to elucidate the mechanism underlying the progression of CF lung vascular disease. Methods: As part of an ongoing clinical trial, we performed pulmonary vascular morphometry and reconstructed the pulmonary vasculature of 40 individuals with CF. Furthermore, we used a vessel-on-a-chip model to examine the effects of shear stress on CFTR-defective ECs. We also investigated how CFTR dysfunction modulates the activity of the calcium-permeable mechanosensitive channels TRPV4 and PIEZO1. Results: Pulmonary vascular morphometry revealed a loss of small pulmonary blood vessels in CF patients with severe lung disease. Microfluidics studies established a shear stress-dependent mechanism of endothelial barrier failure in CF involving TRPV4 and its downstream calcium (open full item for complete abstract)

Committee: Roger Worrell Ph.D. (Committee Chair); Kyu Shik Mun Ph.D. (Committee Member); Anjaparavanda Naren Ph.D. (Committee Member); Bryan Mackenzie Ph.D. (Committee Member); Kathryn Wikenheiser-Brokamp M.D. (Committee Member); Anil Jegga DVM MRe (Committee Member) Subjects: Cellular Biology

PhD, University of Cincinnati, 2023, Medicine: Biostatistics (Environmental Health)

In recent years, advancements in real-time prediction have been achieved by introducing a more flexible term representing a non-stationary stochastic process to replace the classic random slope in the linear mixed effects models. The resulting model has been used to form predictive probabilities for clinically relevant target functions involving rates of change in the mean response function for people with cystic fibrosis (CF). However, data patterns are changing over time, especially with the introduction of ivacaftor treatment in 2012 followed by other highly effective modulator therapies. In this dissertation, I focused on evaluating the epidemiologic impact of secular trends in CF care and treatments on acute lung decline prediction and characterized the changing patterns. Specifically, I evaluated the performance of predicting rapid lung decline events through a novel data-driven definition. There are often multiple, related, noisily-measured outcomes that are critical to monitoring and predicting disease progression of individuals over time. However, the current approach has been limited to a single outcome. Considering the case of two outcomes, I propose a bivariate mixed effects model utilizing integrated Brownian motion for each mean response function. Estimation of the proposed model was implemented through a combined approach of the Newton-Raphson and Fisher Scoring algorithm and profile likelihood. I also propose a bivariate target function that simultaneously predicts under the two-outcome scenario based on clinically meaningful thresholds of rates of change. This novel approach is applied to achieve real-time prediction of key changes in nutrition and lung function for children with CF who are followed in a national patient registry.

Committee: RhondaRhonda SzczesniakSzczesniak Ph.D.Ph.D. (Committee Chair); Marepalli Rao Ph.D. (Committee Member); Roman Jandarov Ph.D. (Committee Member); Richard Brokamp Ph.D. (Committee Member); Marepalli Rao Ph.D. (Committee Member) Subjects: Biostatistics

PhD, University of Cincinnati, 2022, Medicine: Biostatistics (Environmental Health)

Cystic fibrosis (CF) is an autosomal recessive disorder affecting approximately 30,000 people in the United States. Patients with CF develop chronic lung infections and develop recurrent respiratory symptoms called pulmonary exacerbations (PE). Individual PE symptoms may substantially vary according to changes in lung function, nutrition and other clinical factors, and there is no consensus on timely treatment initiation. The Early Intervention in Cystic Fibrosis Exacerbation Study (eICE) was designed to determine whether early treatment of PE events is beneficial. To mitigate exacerbations, it is important to identify and control specific environmental factors such as climate and air pollution. We develop a case-crossover design to evaluate whether pulmonary exacerbations are associated with daily fluctuations in weighted PM2.5 estimates. The case-crossover design allows for temporal variables between case and control periods and controls for many potential confounders that do not change in the conditional logistic regression model. Our results demonstrate a positive association between daily weighted PM2.5 estimates and the prevalence of pulmonary exacerbations with a suitable washout period. Lag models capture the exposure effect up to three days prior to the onset of these exacerbations. The advantages, issues, and possible solutions of implementing a case-crossover design are also investigated. Several important drawbacks of the case-crossover study design require the understanding of the mechanics why CF patients develop PE events. We develop a simulation to replicate the case-crossover eICE study to examine the effects of the prevalence of PE events by a participants baseline risk, PM2.5, effect size, and washout. The case-crossover simulation generates cases by following a cohort of individuals with CF every day and then implements the case-crossover design to summarize the association between pulmonary exacerbation prevalence and PM2.5 exposure. We c (open full item for complete abstract)

Committee: Marepalli Rao Ph.D. (Committee Member); Rhonda Szczesniak Ph.D. (Committee Member); Richard Brokamp Ph.D. (Committee Member) Subjects: Environmental Health

MS, University of Cincinnati, 2022, Medicine: Biostatistics (Environmental Health)

BACKGROUND: Environmental exposures and community characteristics have been linked to rapid lung function decline and other adverse pulmonary outcomes in people with cystic fibrosis (CF). Geomarkers, the measurements of these exposures, have been linked to patient outcomes in other respiratory diseases, though broad-based geomarker studies are lacking and it is unknown which geomarkers will have the greatest predictive potential for rapid decline and pulmonary exacerbation (PEx) in CF. OBJECTIVE: A retrospective longitudinal cohort study was performed to determine whether and which geomarkers would be chosen via novel Bayesian joint covariate selection approaches and to compare the predictive performance of the resultant models for onset of PEx. METHODS: Non-stationary Gaussian linear mixed effects models were fitted to data from 151 cystic fibrosis patients aged 6 – 20 receiving care at the Cincinnati Children's Hospital Cystic Fibrosis Center (2007-2017). The outcome of interest was forced expiratory volume in 1 second of percent predicted (FEV1pp). Target functions were used to predict PEx onset according to an established definition based on drops in FEV1pp. Covariates included 11 clinical/demographic characteristics (age, sex, number of PEx-defined events within previous year, F508del mutation, pancreatic insufficiency, MEDICAID insurance use, BMI percentile, PA infection, MRSA infection, CF-related diabetes mellitus, and the number of hospital visits within the previous year), and 45 geomarkers comprising 8 categories (socioeconomic status, access to care, roadway proximity, crime, land cover, impervious descriptors, weather, and air pollution). Joint selection of covariates for predictive models was achieved using four Bayesian penalized regression models (elastic-net, adaptive lasso, ridge, and lasso). Unique covariate selections at both the 95% and 90% credible intervals (CIs) were fit to a linear mixed effects model with non-stationary stocha (open full item for complete abstract)

Committee: Marepalli Rao Ph.D. (Committee Member); Rhonda Szczesniak Ph.D. (Committee Member) Subjects: Statistics

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

Lung cancer is leading cause of cancer-related deaths in the United States with 5-year survival rate of 18.6%. This is due to late detection of lung cancer and problems in screening for lung cancer. Indeterminate pulmonary nodules (IPNs) are pulmonary nodules size between 7-20mm diameter solid nodules. 90% of IPNs are incidentally found and they are hard to diagnosis due to their small size and current diagnosis methods such as CT, PET scans and biopsy involve high exposure to radiation or invasive and could lead to complications. The majority of lung cancer patients have non-small cell lung cancer (NSCLC) and 64% of these patients exhibit driver mutations such as epithelial growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK) and Ras mutations. These patients have shown to have improved survival rate if they are treated with targeted therapies directed against the driver mutations. Although these patients initially show strong response to targeted therapies, most patients develop resistance to these targeted treatments through secondary point mutation and epithelial to mesenchymal transition (EMT). The lung is a dynamic organ where alveolar epithelial cells are normally exposed to significant mechanical forces (i.e. ~8% cyclic strain, transmural pressure and shear stress) while primary lung tumor cells experience a 40-fold decrease in these mechanical forces/strain. Although biomechanical factors in the tumor microenvironment have been shown to be a significant driver of cancer progression, there is limited information about how biophysical forces alters drug sensitivity in lung adenocarcinoma cells. Based on the known importance of mechanical forces/strain on lung injury and repair and the significant difference in cyclic strain applied to normal and cancer cells in the lung, we hypothesized that cyclic mechanical strain would activate important oncogenic pathways and alter drug sensitivity. Although local mechanical properties of the lung tumor may (open full item for complete abstract)

Committee: Ghadiali Samir Dr. (Advisor); Joshua Englert Dr. (Committee Member); Arunark Kolipaka Dr. (Committee Member) Subjects: Biomedical Engineering

Master of Science, The Ohio State University, 2021, Psychology

As noted by Swigris and colleagues (2015), health-related quality of life (HRQoL) among individuals diagnosed with Interstitial Lung Disease (ILD) is known to impact functioning across a range of dimensions. To date, research on HRQoL in ILD has focused on physiological functioning, symptoms, functional status, and psychological functioning. However, quality of life (QoL) may include additional relevant domains such as social support and health perceptions. This study was designed to provide a more holistic perspective of QoL among individuals with ILD, by assessing six quality of life domains (biological and physiological functioning, symptom status, functional status, health perceptions, social support, and psychological functioning) identified in the Cleary and Wilson HRQoL model (1995). Forty participants with ILD were recruited from patients being treated in an outpatient clinic for pulmonary diseases. Participants completed HRQoL questionnaires and blood sampling for analysis of inflammatory biomarkers. Primary QoL measures included illness-specific and generic physical and mental quality of life. The primary approach to data analyses included an examination of the interrelationships among HRQoL domains, followed by hierarchical regression analyses to determine whether perceptual, social, or psychological variables predicted additional variance in QoL when controlling for select physiological variables. A final analysis compared QoL outcomes across ILD diagnostic groups to determine whether greater disease burden was experienced by those with faster compared to slower illness progression. Results indicated that illness-specific and generic QoL outcomes were associated with the six HRQoL dimensions. Novel findings included a positive association of generic mental QoL with social support, as well as positive associations of health perceptions with illness-specific QOL and with generic physical and mental QoL. Domains of illness perceptions and psychologica (open full item for complete abstract)

Committee: Charles Emery (Advisor) Subjects: Health Care; Health Sciences; Psychology

PhD, University of Cincinnati, 2020, Medicine: Cancer and Cell Biology

The Forkhead box (Fox) family transcription factors are critical regulators of development and disease. The studies described within this dissertation focus on novel cell specific roles of FOXM1 and FOXF1, two members of the Fox transcription factor family, in the progression of lung diseases. FOXM1 plays a crucial role in cell cycle progression and is well characterized in tumorigenesis and tumor progression. FOXM1 in pulmonary epithelial cells, and fibroblasts has been shown to regulate pulmonary fibrosis. However, the regulation of pulmonary fibrosis by FOXM1 in macrophages is not known. In the first study, we identify that FOXM1 is induced in macrophages of idiopathic pulmonary fibrosis (IPF) patients and bleomycin-induced fibrotic mouse lungs. Genetic deletion of Foxm1 in macrophages exacerbates bleomycin-induced pulmonary fibrosis in mice. Deletion of Foxm1 from macrophages results in increased activation of p38 MAPK pathway, causing increased production of inflammatory cytokines. This results in increased fibroblast activation and proliferation, contributing to increased collagen deposition and progression of pulmonary fibrosis. FOXM1 directly binds to Dusp1 promoter, a negative regulator of p38 MAPK pathway, and activates transcription of the gene. Therefore, loss of FOXM1 in macrophages decreases DUSP1 and increases activation of p38 MAPK pathway leading to increased pulmonary fibrosis. This study suggests an important limitation of using pharmacological FOXM1 inhibitors in IPF. The second study focuses on FOXF1, a mesenchyme-specific transcription factor, required for lung development and homeostasis. FOXF1 is highly expressed in pulmonary endothelial cells and is required for maintaining endothelial barrier function. However, the role of endothelial FOXF1 in lung cancer progression is not known. This study identifies loss of FOXF1 in endothelial cells within lung tumor associated vasculature of NSCLC patients and mouse models of lung cancer. Genetic deple (open full item for complete abstract)

Committee: Tanya Kalin M.D. Ph.D. (Committee Chair); Theresa Alenghat Ph.D. (Committee Member); Chunying Du Ph.D. (Committee Member); Saulius Sumanas Ph.D. (Committee Member); Susan Waltz Ph.D. (Committee Member) Subjects: Biology

Bachelor of Science, Walsh University, 2020, Honors

Background and Purpose: Cystic fibrosis (CF) is a multisystem genetic disease that, while historically known as a pediatric condition, has come to impact many adults as life expectancy with the disease increases. Patients with CF experience a cycle of inflammation and infection in the lungs, which can lead to hospitalization due to a pulmonary exacerbation. Physical therapy (PT) is a recommended part of care for patients with CF, but few evidence-based guidelines exist on PT for this population. The purpose of this case series is to describe the PT interventions for patients with CF admitted to the hospital for a pulmonary exacerbation and to discuss the patients' outcomes. Cases: The subjects for this retrospective case series were female adults whose forced expiratory volume in 1 second (FEV1) of 40% or less placed them in the severe CF disease state. They were all admitted to the same CF care center for a pulmonary exacerbation and received PT during the episode of care. The patients presented with impaired ventilation, gas exchange, strength, activity tolerance, and endurance. Their lengths of hospital stay ranged from 13 to 32 days, and patients participated in between 4 and 15 PT sessions each. The most commonly performed PT interventions were breathing exercises, aerobic exercise, and strength training. While a variety of functional outcome measures were used, physical therapists utilized the five-times sit-to-stand (5xSTS) test with all three patients. Results: Patients tolerated a variety of modes of exercise with few noted adverse reactions, mainly oxygen desaturation. By the end of the episode of care, all three patients, by varying amounts, had an increased FEV1 as compared to admission and a positive change in the 5xSTS by discharge from the hospital.

Committee: Alysha Walter PT, DPT, CCS (Advisor); Jaime Paz PT, DPT, MS (Advisor) Subjects: Health; Health Care; Health Sciences; Medicine; Physical Therapy

Doctor of Philosophy, The Ohio State University, 1982, Graduate School

Committee: Not Provided (Other) Subjects: Biology

Doctor of Philosophy, The Ohio State University, 2014, Biomedical Engineering

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by the accumulation of scar tissue within the lung interstitium caused by excessive extracellular matrix (ECM) production and remodeling by myofibroblasts. There are no approved treatments available and the standard of care focuses on supportive therapies and lung transplant. Previous studies have shown that ECM substrates affect cellular proliferation, differentiation, motility, and invasion which are all important components of scar tissue production in IPF, highlighting the importance of physiological in vitro models of IPF. It is known that cells can communicate over long distances on biological ECMs compared to linear elastic substrates; however, researchers continue to debate whether the fibers or strain-hardening property of the biological materials cause the increased cellular sensing. Thus, we have developed computational models to test the effects of fibers and strain-hardening materials independently which cannot be performed in an in vitro setting. The ets (E twenty-six) family of transcription factors regulates cellular proliferation, differentiation, migration, and ECM production. Previously, phosphorylated ets-2 has been found in human IPF lung biopsies and an ets-2 mutant mouse (where ets-2 phosphorylation was blocked) was protected from bleomycin induced pulmonary fibrosis; however, it is unclear how the ets-2 mutation prevents fibrosis. Thus, we utilized an ex vivo microenvironment assay to measure expression of pro-fibrotic genes in addition to performing multiple cellular biomechanical assays. Major findings: 1. ECM fibers were responsible for stress transmission between cells, a property facilitated by cellular remodeling of the ECM fibers into bundles 2.Strain-hardening materials did not increase stress transmission between cells compared to the fibrous or linear elastic ECMs Thus, ECM fibers which are remodeled into bundles are responsible for transmitting (open full item for complete abstract)

Committee: Samir Ghadiali Ph.D. (Advisor); Keith Gooch Ph.D. (Committee Member); Richard Hart Ph.D. (Committee Member); Heather Powell Ph.D. (Committee Member) Subjects: Biomechanics; Biomedical Engineering; Biomedical Research

PhD, University of Cincinnati, 2013, Medicine: Molecular and Developmental Biology

The transcription factor Foxm1 is a critical regulator of development and disease. Foxm1's canonical function as cell cycle regulator promotes development of many organ systems and is essential for cancer progression. However, recent years have highlighted proliferation-independent functions of Foxm1 that depend upon cellular context. The studies described within were conducted to identify novel functions of Foxm1 during onset of pulmonary fibrosis and cancer metastatic dissemination. In a radiation-induced model of pulmonary fibrosis, Foxm1 drives progression of this disease by increasing inflammation and myofibroblast activation. Foxm1 directly regulates epithelial-to-mesenchymal transition (EMT) via regulation of the transcription factor Snail1. Lineage-tracing analysis demonstrated that over-expression of Foxm1 can increase EMT events during fibrosis. Foxm1-regulated EMT is also critical for cancer cell invasion during metastasis. Foxm1 regulates invasive and tumor-initiating abilities of cancer cells in vitro. Expression of Foxm1 late during adenoma formation induces progression to more advanced lung adenocarcinoma. Mechanistically, Foxm1 promotes a mucinous adenocarcinoma phenotype, in part, by expression of cancer stem cell gene Sox2. These studies identify previously unknown functions of Foxm1 during disease onset.

Committee: Tanya Kalinichenko Ph.D. (Committee Chair); Vladimir Kalinichenko M.D., Ph.D. (Committee Member); Timothy Weaver Ph.D. (Committee Member); Jeffrey Whitsett M.D. (Committee Member); Aaron Zorn Ph.D. (Committee Member) Subjects: Molecular Biology

MS, University of Cincinnati, 2008, Medicine : Epidemiology (Environmental Health)

Purpose: Children with cystic fibrosis (CF) have a high prevalence of gastroesophageal reflux disease (GERD). As GERD is associated with chronic respiratory symptoms and feeding problems, fundoplication is often performed in children with CF. Although the outcomes of fundoplication have been described across diverse pediatric groups, there is no published experience with CF. Methods: The records of 25 children with CF who underwent fundoplication in our center were reviewed. Data was collected regarding symptoms diagnostic testing, and complications related to fundoplication. Nutritional parameters and pulmonary function were compared before and after fundoplication. Results: There was no mortality associated with fundoplication but 12% had complications that required a subsequent surgical procedure. While 28% were able to discontinue their anti-reflux medications 48% developed symptoms of recurrent GERD. Overall there was no change in BMI, BMI percentile, or FEV1 slope following fundoplication. Children who had an FEV1 <60% predicted at the time of fundoplication exhibited an improvement in FEV1 slope compared to those with FEV1 >or = 60% (+5.3%/year vs. -8.6%/year, P=0.004). Conclusion: The complication rate of fundoplication is similar to what has been reported in large series' in children without CF. There is a high rate of recurrent GERD and little apparent benefit for either nutritional or pulmonary outcomes. The observed difference on FEV1 slope, in those with moderate-severe vs. mild lung disease, highlights the need to thoroughly evaluate the role of fundoplication in children with CF.

Committee: Dr. James Heubi (Advisor) Subjects:

Doctor of Philosophy, The Ohio State University, 2004, Pathology

Monocytes are precursors to tissue macrophages. We performed microarray expression analysis to determine the genetic expression profiles of peripheral blood monocytes (PBM) and alveolar macrophages (AM). Our data indicates that several hundred genes are differentially regulated in PBM and AM. These include genes involved in cellular scavenging, intracellular signaling pathways, cellular survival and/or differentiation. We observed that the chemokine receptor expression profiles of PBM and AM differed in the gene array analysis, and confirmed these results by reverse transcriptase polymerase chain reaction, flow cytometry and functional analyses. Our data indicates that circulating monocytes express the chemokine receptors CCR1 and CCR2, and that monocytes functionally respond by migrating toward both MCP-1 and MIP-1a. In contrast, alveolar macrophages do not express CCR1 or CCR2, but do express the MIP-1a chemokine receptor CCR5. AM did not respond to MCP-1 but did respond to MIP-1a in a migration assay. The addition of an anti-CCR5 blocking antibody completely abrogated MIP-1a-induced migration in AM, but did not affect monocytes. These data may be helpful in understanding the regulated recruitment of inflammatory cells in areas of lung inflammation. This data is relevant to human disease, as in pulmonary fibrosis (PF) high concentrations of MCP-1 are found in the lung lavage fluid from affected patients but not in normal volunteers. PF is a serious lung disease characterized by progressive scarring of the lung tissue, eventually leading to hypoxemia and death. Prognosis is worsened in patients with more monocytes and macrophages in their lungs. We used an animal model of bleomycin-induced PF to examine the role of Macrophage Colony-Stimulating Factor (M-CSF) in the development of this disease. We chose this model because mice that are genetically deficient in M-CSF have decreased numbers of circulating monocytes and tissue macrophages, and provide a useful model f (open full item for complete abstract)

Committee: Clay Marsh (Advisor) Subjects:

Doctor of Philosophy, Case Western Reserve University, 2010, Genetics

Cystic fibrosis (CF) is a common, phenotypically variable disease caused by mutations in the CFTR gene, which encodes a cAMP-dependent chloride channel found in many cell types. Symptoms are primarily gastrointestinal and pulmonary in nature, with the pulmonary disease accounting for the majority of the mortality in CF. A great deal of effort has been dedicated toward the characterization of the genetic contribution to the disease variance, with many modifier genes for cystic fibrosis having been described. We have undertaken a novel approach to the identification of cystic fibrosis modifier genes by establishing the Gene Modifier Study (GMS), which utilizes a candidate gene approach to compare the genetic profile of the most severe CF patients to that of the most mild CF patients. Transforming growth factor beta-1 (TGF-β1), beta-2 adrenergic receptor (ADRB2) and endothelin receptor type A (EDNRA) are candidate CF modifiers described here. Variants within the TGF-β1 promoter and codon 10 demonstrated a nominal association with CF severity, though the mechanism behind this association has not been elucidated. Variants within ADRB2 associated with CF patient response to inhaled bronchodilators, but not with long-term disease severity and survival. One of the genes that has shown reproducible genetic association with CF phenotype, is the EDNRA gene. EDNRA binds endothelin-1 (ET-1) in airway smooth muscle cells to stimulate smooth muscle contraction and cell proliferation. Variants within the 3' untranslated region and 5'untranslated region of this gene demonstrated a significant association with pulmonary function levels particularly in females. The combined haplotype between the two positions was a strong predictor of CF severity in females. In follow-up studies performed on primary human tracheal smooth muscle cells, we discovered that the alleles associating with worse CF pulmonary disease, were also found to be associated with increased mRNA message levels, and in (open full item for complete abstract)

Committee: Mitchell Drumm (Advisor); Helen Salz (Committee Chair); Joseph Nadeau (Committee Member); Georgia Wiesner (Committee Member); Elliott Dasenbrook (Committee Member) Subjects: Genetics