Digital Commons Network^™

The Bile Acid Induced Hepatokine Orosomucoid Suppresses Adipocyte Differentiation, Sung Ho Lee, Jong Min Choi, Sung Yun Jung, Aaron R Cox, Sean M Hartig, David D Moore, Kang Ho Kim

Faculty, Staff and Students Publications

Bile acids have recently emerged as key metabolic hormones with beneficial impacts in multiple metabolic diseases. We previously discovered that hepatic bile acid overload distally modulates glucose and fatty acid metabolism in adipose tissues to exert anti-obesity effects. However, the detailed mechanisms that explain the salutary effects of serum bile acid elevation remain unclear. Here, proteomic profiling identified a new hepatokine, Orosomucoid (ORM) that governs liver-adipose tissue crosstalk. Hepatic ORMs were highly induced by both genetic and dietary bile acid overload. To address the direct metabolic effects of ORM, purified ORM proteins were administered during adipogenic differentiation of 3T3-L1 cells …

Adipocyte-Specific Ablation Of Pu1 Promotes Energy Expenditure And Ameliorates Metabolic Syndrome In Aging Mice, Ke Yun Chen, Alejandra De Angulo, Xin Guo, Aditya More, Scott A Ochsner, Eduardo Lopez, David Saul, Weijun Pang, Yuxiang Sun, Neil J Mckenna, Qiang Tong

Faculty, Staff and Students Publications

Objective: Although PU.1/Spi1 is known as a master regulator for macrophage development and function, we have reported previously that it is also expressed in adipocytes and is transcriptionally induced in obesity. Here, we investigated the role of adipocyte PU.1 in the development of the age-associated metabolic syndrome.

Methods: We generated mice with adipocyte-specific PU.1 knockout, assessed metabolic changes in young and older adult PU.1^fl/fl (control) and AdipoqCre PU.1^fl/fl (aPU.1KO) mice, including body weight, body composition, energy expenditure, and glucose homeostasis. We also performed transcriptional analyses using RNA-Sequencing of adipocytes from these mice.

Results: aPU.1KO mice have elevated energy …

Intrapulmonary Administration Of Purified Neil2 Abrogates Nf-Κb-Mediated Inflammation, Nisha Tapryal, Shandy Shahabi, Anirban Chakraborty, Koa Hosoki, Maki Wakamiya, Gobinda Sarkar, Gulshan Sharma, Victor J Cardenas, Istvan Boldogh, Sanjiv Sur, Gourisankar Ghosh, Tapas K Hazra

Faculty, Staff and Students Publications

Aberrant or constitutive activation of nuclear factor kappa B (NF-κB) contributes to various human inflammatory diseases and malignancies via the upregulation of genes involved in cell proliferation, survival, angiogenesis, inflammation, and metastasis. Thus, inhibition of NF-κB signaling has potential for therapeutic applications in cancer and inflammatory diseases. We reported previously that Nei-like DNA glycosylase 2 (NEIL2), a mammalian DNA glycosylase, is involved in the preferential repair of oxidized DNA bases from the transcriptionally active sequences via the transcription-coupled base excision repair pathway. We have further shown that Neil2-null mice are highly sensitive to tumor necrosis factor α (TNFα)- and lipopolysaccharide-induced …

Small-Molecule Inhibitor Of Af9/Enl-Dot1l/Af4/Aff4 Interactions Suppresses Malignant Gene Expression And Tumor Grow, Fangrui Wu, Shenyou Nie, Yuan Yao, Tong Huo, Xin Li, Xiaowei Wu, Jidong Zhao, Yi-Lun Lin, Yinjie Zhang, Qianxing Mo, Yongcheng Song

Faculty, Staff and Students Publications

Chromosome translocations involving mixed lineage leukemia (MLL) gene cause acute leukemia with a poor prognosis. MLL is frequently fused with transcription cofactors AF4 (~35%), AF9 (25%) or its paralog ENL (10%). The AHD domain of AF9/ENL binds to AF4, its paralog AFF4, or histone-H3 lysine-79 (H3K79) methyltransferase DOT1L. Formation of AF9/ENL/AF4/AFF4-containing super elongation complexes (SEC) and the catalytic activity of DOT1L are essential for MLL-rearranged leukemia. Protein-protein interactions (PPI) between AF9/ENL and DOT1L/AF4/AFF4 are therefore a potential drug target.

Methods: Compound screening followed by medicinal chemistry was used to find inhibitors of such PPIs, which were examined for their biological …

A Novel Statistical Method For Interpreting The Pathogenicity Of Rare Variants, Jun Wang, Hehe Liu, Renae Elaine Bertrand, Alejandro Sarrion-Perdigones, Yezabel Gonzalez, Koen J T Venken, Rui Chen

Faculty, Staff and Students Publications

PURPOSE: To achieve the ultimate goal of personalized treatment of patients, accurate molecular diagnosis and precise interpretation of the impact of genetic variants on gene function is essential. With sequencing cost becoming increasingly affordable, the accurate distinguishing of benign from pathogenic variants becomes the major bottleneck. Although large normal population sequence databases have become a key resource in filtering benign variants, they are not effective at filtering extremely rare variants.

METHODS: To address this challenge, we developed a novel statistical test by combining sequencing data from a patient cohort with a normal control population database. By comparing the expected and …

The E3 Ligase Traf4 Promotes Igf Signaling By Mediating Atypical Ubiquitination Of Irs-1, Wenjuan Yu, Ramesh Singh, Zhao Wang, Bert W O'Malley, Ping Yi

Faculty, Staff and Students Publications

Insulin-like growth factor (IGF) is a potent mitogen that activates the IGF receptor (IGFR)/insulin receptor substrate (IRS) axis, thus stimulating growth in normal cells and uncontrolled cell proliferation in cancer. Posttranslational modifications of IRS such as ubiquitination tightly control IGF signaling, and we previously identified IRS-1 as a potential substrate for the E3 ubiquitin ligase TRAF4 using an unbiased screen. Here we provide evidence that TRAF4-mediated ubiquitination of IRS-1 is physiologically relevant and crucial for IGF signal transduction. Through site-directed mutagenesis we found that TRAF4 promotes an atypical K29-linked ubiquitination at the C-terminal end of IRS-1. Its depletion abolishes AKT …

Lrrtm4 Is A Member Of The Transsynaptic Complex Between Rod Photoreceptors And Bipolar Cells, Melina A Agosto, Theodore G Wensel

Faculty, Staff and Students Publications

Leucine rich repeat transmembrane (LRRTM) proteins are synaptic adhesion molecules with roles in synapse formation and signaling. LRRTM4 transcripts were previously shown to be enriched in rod bipolar cells (BCs), secondary neurons of the retina that form synapses with rod photoreceptors. Using two different antibodies, LRRTM4 was found to reside primarily at rod BC dendritic tips, where it colocalized with the transduction channel protein, TRPM1. LRRTM4 was not detected at dendritic tips of ON-cone BCs. Following somatic knockout of LRRTM4 in BCs by subretinal injection and electroporation of CRISPR/Cas9, LRRTM4 was abolished or reduced in the dendritic tips of transfected …

Trace Element Concentrations In Blood And Scute Tissues From Wild And Captive Hawaiian Green Sea Turtles (Chelonia Mydas), Katherine R Shaw, Jennifer M Lynch, George H Balazs, T Todd Jones, Jeff Pawloski, Marc R Rice, Amanda D French, Jing Liu, George P Cobb, David M Klein

Faculty, Staff and Students Publications

Sea turtles are exposed to trace elements through water, sediment, and food. Exposure to these elements has been shown to decrease immune function, impair growth, and decrease reproductive output in wildlife. This study compares trace element concentrations in green turtles in captivity at Sea Life Park Hawaii (n = 6) to wild green turtles in Kapoho Bay, HI (n = 5 to 7). Blood and scute samples were collected and analyzed for eleven elements via inductively coupled plasma-mass spectrometry (ICP-MS). Selenium was significantly greater (p < 0.05) in the blood of captive turtles compared to wild turtles, while V, Ni, and Pb were significantly greater in the blood of wild turtles. In scute, V, Cu, Se, and Cr were significantly greater in captive turtles, while As was significantly greater in wild turtles. Pelleted food fed to the captive turtles and representative samples of the wild turtle diet were analyzed via ICP-MS to calculate trophic transfer factors and daily intake values. Wild turtles had greater estimated daily intake than captive turtles for all elements except Cu and Se. Because captive turtles are fed a diet very different from their wild counterparts, captive turtles do not represent control or reference samples for chemical exposure studies in wild turtles. No toxic thresholds are known for sea turtles, but rehabilitation and managed care facilities should monitor sea turtle elemental concentrations to ensure the animals’ health.

Secretion Of Von Willebrand Factor And Suppression Of Adamts-13 Activity By Markedly High Concentration Of Ferritin, Dalia A Bashir, Qi Da, Subhashree Pradhan, Nitin Sekhar, Christian Valladolid, Fong Lam, Danielle Guffey, Jordana Goldman, Moreshwar S Desai, Miguel A Cruz, Carl Allen, Trung C Nguyen, K Vinod Vijayan

Faculty, Staff and Students Publications

Hyperferritinemia is associated with poor outcomes in critically ill patients with sepsis, hemophagocytic lymphohistiocytosis (HLH), macrophage activation syndromes (MAS) and coronavirus disease 19 (COVID-19). Autopsies of hyperferritinemic patients that succumbed to either sepsis, HLH, MAS or COVID-19 have revealed disseminated microvascular thromboses with von Willebrand factor (VWF)-, platelets-, and/or fibrin-rich microthrombi. It is unknown whether high plasma ferritin concentration actively promotes microvascular thrombosis, or merely serves as a prognostic biomarker in these patients. Here, we show that secretion of VWF from human umbilical vein endothelial cells (HUVEC) is significantly enhanced by 100,000 ng/ml of recombinant ferritin heavy chain protein (FHC). …

Alcohol Consumption And The Risk Of Gastric Intestinal Metaplasia In A Us Veterans Population, Hudson M Holmes, Andre G Jove, Mimi C Tan, Hashem B El-Serag, Aaron P Thrift

Faculty, Staff and Students Publications

BACKGROUND: Chronic alcohol use is a risk factor for non-cardia gastric adenocarcinoma. However, it is less well understood whether alcohol use is a risk factor for premalignant mucosal changes, namely gastric intestinal metaplasia. We examined the association between various parameters of alcohol use and risk of gastric intestinal metaplasia.

METHODS: We used data from 2084 participants (including 403 with gastric intestinal metaplasia) recruited between February 2008-August 2013 into a cross-sectional study at the Michael E. DeBakey Veterans Affairs Medical Center in Houston, Texas. All participants underwent a study upper endoscopy with systematic gastric mapping biopsies. Cases had intestinal metaplasia on …

Protein-Functionalized Poly(Ethylene Glycol) Hydrogels As Scaffolds For Monolayer Organoid Culture, Reid L Wilson, Ganesh Swaminathan, Khalil Ettayebi, Carolyn Bomidi, Xi-Lei Zeng, Sarah E Blutt, Mary K Estes, K Jane Grande-Allen

Faculty, Staff and Students Publications

Stem cell-derived, organotypic in vitro models, known as organoids, have emerged as superior alternatives to traditional cell culture models due to their unparalleled ability to recreate complex physiological and pathophysiological processes. For this reason, they are attractive targets of tissue-engineering efforts, as constructs that include organoid technology would be expected to better simulate the many functions of the desired tissue or organ. While the 3D spheroidal architecture that is the default architecture of most organoid models may be preferred for some applications, 2D monolayer arrangements remain the preferred organization for many applications in tissue engineering. Therefore, in this work, we …

Identification Of Deep-Intronic Splice Mutations In A Large Cohort Of Patients With Inherited Retinal Diseases, Xinye Qian, Jun Wang, Meng Wang, Austin D Igelman, Kaylie D Jones, Yumei Li, Keqing Wang, Kerry E Goetz, David G Birch, Paul Yang, Mark E Pennesi, Rui Chen

Faculty, Staff and Students Publications

High throughput sequencing technologies have revolutionized the identification of mutations responsible for a diverse set of Mendelian disorders, including inherited retinal disorders (IRDs). However, the causal mutations remain elusive for a significant proportion of patients. This may be partially due to pathogenic mutations located in non-coding regions, which are largely missed by capture sequencing targeting the coding regions. The advent of whole-genome sequencing (WGS) allows us to systematically detect non-coding variations. However, the interpretation of these variations remains a significant bottleneck. In this study, we investigated the contribution of deep-intronic splice variants to IRDs. WGS was performed for a cohort …

Long Noncoding Rnas And Their Therapeutic Promise In Diabetic Nephropathy, Juan D Coellar, Jianyin Long, Farhad R Danesh

Faculty, Staff and Students Publications

Recent advances in large-scale RNA sequencing and genome-wide profiling projects have unraveled a heterogeneous group of RNAs, collectively known as long noncoding RNAs (lncRNAs), which play central roles in many diverse biological processes. Importantly, an association between aberrant expression of lncRNAs and diverse human pathologies has been reported, including in a variety of kidney diseases. These observations have raised the possibility that lncRNAs may represent unexploited potential therapeutic targets for kidney diseases. Several important questions regarding the functionality of lncRNAs and their impact in kidney diseases, however, remain to be carefully addressed. Here, we provide an overview of the main …

Alpha-Single Chains Of Collagen Type Vi Inhibit The Fibrogenic Effects Of Triple Helical Collagen Vi In Hepatic Stellate Cells, Christian Freise, Hyunho Lee, Christopher Chronowski, Doug Chan, Jessica Cziomer, Martin Rühl, Tarkan Dagdelen, Maik Lösekann, Ulrike Erben, Andre Catic, Werner Tegge, Detlef Schuppan, Rajan Somasundaram, Ergun Sahin

Faculty, Staff and Students Publications

The interaction of extracellular matrix (ECM) components with hepatic stellate cells (HSCs) is thought to perpetuate fibrosis by stimulating signaling pathways that drive HSC activation, survival and proliferation. Consequently, disrupting the interaction between ECM and HSCs is considered a therapeutical avenue although respective targets and underlying mechanisms remain to be established. Here we have interrogated the interaction between type VI collagen (CVI) and HSCs based on the observation that CVI is 10-fold upregulated during fibrosis, closely associates with HSCs in vivo and promotes cell proliferation and cell survival in cancer cell lines. We exposed primary rat HSCs and a rat …

Risk And Protective Factor Specific To African American Youth And Adolescents: A Systematic Review, Darius Reed, Raymond Dewayne Adams

Journal of Family Strengths

Although existing suicide literature proposes that simply being African American protects against suicide (Nguyen et al., 2017; Street et al., 2012), few studies offer practical insights at mitigating suicidal ideations among African American children and adolescents let alone through a social work perspective (Reed, 2019). As the largest provider of mental health services in the United States (American Counseling Association, 2018), the field of social work research has understudied this phenomenon. While it is true that African Americans have experienced lower rates of suicide when compared to the general population (CDC, 2019), research has not compared the risk and protective …

A Developmental Stage-Specific Network Approach For Studying Dynamic Co-Regulation Of Transcription Factors And Micrornas During Craniofacial Development, Fangfang Yan, Peilin Jia, Hiroki Yoshioka, Akiko Suzuki, Junichi Iwata, Zhongming Zhao

Faculty, Staff and Student Publications

Craniofacial development is regulated through dynamic and complex mechanisms that involve various signaling cascades and gene regulations. Disruption of such regulations can result in craniofacial birth defects. Here, we propose the first developmental stage-specific network approach by integrating two crucial regulators, transcription factors (TFs) and microRNAs (miRNAs), to study their co-regulation during craniofacial development. Specifically, we used TFs, miRNAs and non-TF genes to form feed-forward loops (FFLs) using genomic data covering mouse embryonic days E10.5 to E14.5. We identified key novel regulators (TFs Foxm1, Hif1a, Zbtb16, Myog, Myod1 and Tcf7, and miRNAs miR-340-5p and miR-129-5p) and target genes (

Suicide Ideation, Depression, And Family Structure In Elementary Students, Amanda Koshollek, Collin Wright, Cass Henriques, Makaela Caldwell, Quintin Hunt

Journal of Family Strengths

Background: Little research has been done with suicidality in children under 12 but a growing amount of research suggests family systems play a role in childhood depression and suicide; to date, no measure for suicide ideation exists for children under 12. Aims: The aims of this paper are as follows: (1) to adapt a measure of suicide ideation for children under 12; (2) to test if this measure captures suicide ideation differently than depression; and (3) to determine if with whom children live serves as a protective factor against suicide. Method: A sample of 115 children between ages 8 and …

Large-Scale Characterization Of Drug Responses Of Clinically Relevant Proteins In Cancer Cell Lines, Wei Zhao, Jun Li, Mei-Ju M Chen, Yikai Luo, Zhenlin Ju, Nicole K Nesser, Katie Johnson-Camacho, Christopher T Boniface, Yancey Lawrence, Nupur T Pande, Michael A Davies, Meenhard Herlyn, Taru Muranen, Ioannis K Zervantonakis, Erika Von Euw, Andre Schultz, Shwetha V Kumar, Anil Korkut, Paul T Spellman, Rehan Akbani, Dennis J Slamon, Joe W Gray, Joan S Brugge, Yiling Lu, Gordon B Mills, Han Liang

Faculty, Staff and Students Publications

Perturbation biology is a powerful approach to modeling quantitative cellular behaviors and understanding detailed disease mechanisms. However, large-scale protein response resources of cancer cell lines to perturbations are not available, resulting in a critical knowledge gap. Here we generated and compiled perturbed expression profiles of ∼210 clinically relevant proteins in >12,000 cancer cell line samples in response to ∼170 drug compounds using reverse-phase protein arrays. We show that integrating perturbed protein response signals provides mechanistic insights into drug resistance, increases the predictive power for drug sensitivity, and helps identify effective drug combinations. We build a systematic map of "protein-drug" connectivity …

A Steroid Receptor Coactivator Stimulator (Mcb-613) Attenuates Adverse Remodeling After Myocardial Infarction, Lisa K Mullany, Aarti D Rohira, John P Leach, Jong H Kim, Tanner O Monroe, Andrea R Ortiz, Brittany Stork, M Waleed Gaber, Poonam Sarkar, Andrew G Sikora, Todd K Rosengart, Brian York, Yongcheng Song, Clifford C Dacso, David M Lonard, James F Martin, Bert W O'Malley

Faculty, Staff and Students Publications

Progressive remodeling of the heart, resulting in cardiomyocyte (CM) loss and increased inflammation, fibrosis, and a progressive decrease in cardiac function, are hallmarks of myocardial infarction (MI)-induced heart failure. We show that MCB-613, a potent small molecule stimulator of steroid receptor coactivators (SRCs) attenuates pathological remodeling post-MI. MCB-613 decreases infarct size, apoptosis, hypertrophy, and fibrosis while maintaining significant cardiac function. MCB-613, when given within hours post MI, induces lasting protection from adverse remodeling concomitant with: 1) inhibition of macrophage inflammatory signaling and interleukin 1 (IL-1) signaling, which attenuates the acute inflammatory response, 2) attenuation of fibroblast differentiation, and 3) promotion …

Responsible Fatherhood Program For Native Men: A Mixed-Method Evaluation Of The Good Road Of Life Training, Allyson Kelley, Clayton Small Dr., Maha Charani

Journal of Family Strengths

Objective. The purpose of this evaluation was to document the impact of the Good Road of Life (GRL) Training on Native men from four communities in the Western US. Design: A mixed-method evaluation design was used to document changes in participant responses (N=60) based on pre/post assessments and qualitative data provided. Results. Findings from the quantitative analysis show statistically significant increases in overall mean pre and post knowledge scores for healthy relationships, help seeking behaviors, self-esteem, confidence, and communication skills. Qualitative themes demonstrate the positive impact GRL has on American Indian fathers. Themes related to impacts include …

Case Manager Perceptions Of The Effects Of Caseload Level Reduction In A Child Welfare Agency, Julie Steen

Journal of Family Strengths

This study sought to assess the effects of caseload level reduction in a child welfare agency that provides in-home supervision and out-of-home care in the United States. Focus groups were conducted to collect the perceptions of case managers employed by the agency, which reduced caseloads from the 40s to the 20s. Transcript passages revealed that the perceptions were overwhelmingly positive, with the case managers describing positive impacts for job satisfaction, retention, foster child well-being, permanency, and safety. The case managers also described the mechanisms by which caseload level reduction exerted its effects. Specifically, the reduction allowed for additional/extended home visits …

Beyond The Nuclear Family: A Qualitative Examination Of Extended Family Involvement Among American Indian Families, Ashleigh Coser, Maureen Sullivan, Hannah Espeleta

Journal of Family Strengths

A common practice among American Indian (AI) families, as well as many ethnic minority families, is involving both nuclear and extended family members in raising children. This practice is believed to serve as a protective factor for families against negative outcomes and provide a potential avenue for social support. Several authors have described extended family members being involved in helping to care taking, sharing cultural knowledge and customs, and disciplining youth. As a result, it has been proposed that extended family members help to nurture the parent-child relationship and provide various forms of support to parents. Despite this, the available …

Characterization Of Age-Associated Copd Progression In The Copd Gene Cohort, Lauryn A. Winter

Dissertations and Theses (Open Access)

Chronic obstructive pulmonary disease (COPD) is a progressive and debilitating lung disease affecting primarily older adults. Incidence, morbidity and mortality from COPD are increasing worldwide. The purpose of this study was to determine the associations between age at baseline and markers of disease progression in COPD patients using data generated by the Genetic Epidemiology of COPD (COPD Gene) study. Participants with COPD were stratified by age (younger: age <65 years, elderly: age ≥ 65 years) and disease characteristics (lung function, exercise tolerance, exacerbation history, and comorbidity burden) at baseline and five-year follow up were compared between groups. Associations between age group and changes in these measures were also assessed. Disease characteristics differed significantly between elderly and younger COPD patients at both study visits. Elderly COPD patients had worse lung function and more comorbidities than younger COPD patients, while younger COPD patients reported more dyspnea and more frequent and severe exacerbations than elderly COPD patients. Following covariate adjustment, elderly participants were less likely than younger participants to develop new frequent exacerbations over the study period (relative risk ratio (95% confidence interval): 0.42 (0.20, 0.87)). There were no other significant associations between age group and markers of disease progression. These results suggest that although elderly COPD patients exhibit evidence of more severe lung function impairment than younger COPD patients, the rate of disease progression is similar between elderly and younger patients. However, further exploration is needed to understand the possible contribution of survivorship bias to this finding. Nevertheless, this study supports the importance of early detection and early intervention to slow disease progression and maximize both life expectancy and quality of life for COPD patients.

Breastfeeding Duration And Reasons Given For Early Cessation Of Breastfeeding Among Wic Mothers, Amy Willa

Dissertations and Theses (Open Access)

The Breastfeeding Duration and Reasons for Early Cessation of Breastfeeding Among WIC Mothers study was conducted to describe the duration of and factors associated with early breastfeeding cessation among the Women, Infants, and Children (WIC) population. We collected data from a random sample of WIC medical records, sampling medical records belonging to mothers who initiated breastfeeding an infant but did not breastfeed to 52 weeks. Data were analyzed to answer the questions: How long do WIC mothers breastfeed? What reasons are given during counseling sessions at WIC for early cessation of breastfeeding? Do socio-economic, demographic, or medical factors influence the …

Disruption Of Dna Polymerase Zeta Promotes An Innate Immune Response, Sara Martin

Dissertations and Theses (Open Access)

DNA polymerase ζ (pol ζ) is a specialized polymerase that protects cells from the consequences of DNA damage and stress. Without pol ζ function mammalian cells and yeast are exquisitely sensitive to genotoxic stresses including ultraviolet irradiation and platinum compounds such as the chemotherapeutic agent cisplatin. This elevated sensitivity arises from the central role of pol ζ in lesion bypass. Pol ζ is also required to protect cells from endogenous genomic damage or stress. In primary mammalian cells, the function of pol ζ is required for genome protection and normal proliferation. Immortalized Rev3lknockout (KO) MEFs are under considerable constitutive …

Calcium Dyshomeostasis In Neurodegeneration, Nicholas Emanuel Karagas

Dissertations and Theses (Open Access)

Neurodegenerative diseases, despite constituting a major and growing cause of mortality globally, have few effective treatments. In order to develop novel therapeutics to combat neurodegeneration, a better understanding of the molecular mechanisms underlying these diseases is needed. Neurons rely on Ca²⁺ to mediate many of their unique functions, and aberrant Ca²⁺ signaling has been broadly implicated in neurodegeneration. The goal of this dissertation is to delineate specific examples of Ca²⁺ dyshomeostasis that I have uncovered in Drosophila models of neurodegeneration.

I first define the role a neurodegeneration-associated mutation plays in perturbing presynaptic [Ca²⁺], which is …

Inducible Epithelial Resistance Against Acute Viral Pneumonia And Chronic Asthma, Shradha Wali

Dissertations and Theses (Open Access)

Viral pneumonia remains a global health threat despite worldwide vaccination and therapeutic programs. The influenza pandemic of 1918 and SARS-CoV2 pandemic of 2019-2020 are cautionary reminders demanding the need for novel treatment strategies. Moreover, in addition to causing acute disease, respiratory virus infections are often complicated by chronic lung pathologies, such as asthma induction, progression, and exacerbation. We have reported that mice treated with a combination of inhaled Toll-like receptor (TLR) 2/6 and TLR 9 agonists (Pam2-ODN) to stimulate innate immunity are broadly protected against respiratory pathogens, but the mechanisms underlying this protection remain incompletely elucidated. Here, we show in …

Inducible Epithelial Resistance Against Acute Viral Pneumonia And Chronic Asthma, Shradha Wali

Dissertations and Theses (Open Access)

Viral pneumonia remains a global health threat despite worldwide vaccination and therapeutic programs. The influenza pandemic of 1918 and SARS-CoV2 pandemic of 2019-2020 are cautionary reminders demanding the need for novel treatment strategies. Moreover, in addition to causing acute disease, respiratory virus infections are often complicated by chronic lung pathologies, such as asthma induction, progression, and exacerbation. We have reported that mice treated with a combination of inhaled Toll-like receptor (TLR) 2/6 and TLR 9 agonists (Pam2-ODN) to stimulate innate immunity are broadly protected against respiratory pathogens, but the mechanisms underlying this protection remain incompletely elucidated. Here, we show in …

Hyperpolarized Carbon-13 Magnetic Resonance Measurements Of Tissue Perfusion And Metabolism, Keith Michel

Dissertations and Theses (Open Access)

Hyperpolarized Magnetic Resonance Imaging (HP MRI) is an emerging modality that enables non-invasive interrogation of cells and tissues with unprecedented biochemical detail. This technology provides rapid imaging measurements of the activity of a small quantity of molecules with a strongly polarized nuclear magnetic moment. This polarization is created in a polarizer separate from the imaging magnet, and decays continuously towards a non-detectable thermal equilibrium once the imaging agent is removed from the polarizer and administered by intravenous injection. Specialized imaging strategies are therefore needed to extract as much information as possible from the HP signal during its limited lifetime.

In …

Subclonal Evolution Of Chronic Lymphocytic Leukemia After Allogeneic T Cell Therapies, Haven Garber

Dissertations and Theses (Open Access)

Subclonal evolution of chronic lymphocytic leukemia after allogeneic T-cell therapies

Haven Garber, MD

Advisory Professor: Jeffrey Molldrem, MD

Intratumoral genetic heterogeneity describes the molecular differences among subclones within a tumor and is a major barrier to effective therapy in many solid and liquid cancers, including chronic lymphocytic leukemia (CLL). Rare, treatment-resistant subclones can expand to compose relapsed disease during tumor evolution. Examination of malignant evolution in the context of specific treatment provides insight into the molecular lesions that mediate therapeutic response and resistance. Both chemotherapy and targeted therapy were shown to precipitate CLL subclonal evolution. We hypothesized that allogeneic T-cell …