Medical Sciences Commons^™

The Role Of Adam10 And Adam17 In Humoral And Type 2 Immunity, Joseph C. Lownik

Theses and Dissertations

The proper regulation of inducible costimulator (ICOS) and its ligand (ICOSL) have been shown to be essential for maintaining immune homeostasis. Loss of either protein results in defective humoral immunity, and overexpression of ICOS results in aberrant antibody production resembling lupus. How ICOSL is regulated in response to ICOS interaction is still unclear. We demonstrate that ADAM10 is the primary physiological sheddase of ICOSL in both mouse and human. Using an in vivo system in which ADAM10 is deleted only on B cells (ADAM10^B-/-), elevated levels of ICOSL were seen. This increase is also seen when ADAM10 is …

Glycosaminoglycan Lyases In The Preparation Of Oligosaccharides, Alhumaidi B. Alabbas

Theses and Dissertations

Glycosaminoglycans are heterogeneous polysaccharides that mediate important biological functions. There has been considerable interest in deciphering the precise GAG sequences that are responsible for protein interactions. In fact, several GAG oligosaccharides have been discovered to date as targeting proteins with higher level of specificity. Yet, it has been difficult to develop GAG oligosaccharides as drugs. One of the key reasons for this state of art is that GAG synthesis is extremely challenging and is highly structure-specific. Thus, much of the biology and pharmacology of GAG remains unknown and unexploited to date.

An alternative approach is to prepare GAG oligosaccharides using …

Gastrointestinal Microbiota Modulate Antinociceptive Tolerance Development In Mice With Chronic Morphine Exposure, Ryan A. Mischel

Theses and Dissertations

In October 2017, the United States government declared a state of public health emergency in response to the burgeoning prescription opioid epidemic. Opioid analgesics are the gold standard of therapy for moderate to severe pain, but their clinical utility is greatly limited by analgesic tolerance – a primary driver of diminished pain control and opioid dose escalations. Integral in this process are primary afferent sensory neurons in dorsal root ganglia (DRG), the first-order components of nociceptive sensation. With surmounting evidence that morphine and other narcotics can alter gut microbial composition and promote bacterial translocation to other tissues, a question arises …

The Contribution Of Sarm1 To Axonal Degeneration In Cns Inflammatory Disorders, Daniel C. Njoku

Theses and Dissertations

BACKGROUND: Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) that results in demyelination and axonal loss. Efficiently targeting mechanisms of axonal degeneration in MS has the potential to reduce disability but remains an unmet need. Prior research has identified the protein sterile alpha and TIR motif containing 1 (SARM1) as a critical factor that promotes axonal destruction in the program of axonal degeneration known as Wallerian degeneration. SARM1 inactivation reduces axonal degeneration in a variety of contexts including traumatic and toxic injury, but it remains unknown to what extent SARM1 is involved in axonal degeneration …

Effects Of The Na-Cl Co-Transporter (Ncc) In Western Diet Induced Metabolic And Cardiac Dysfunction, Zachary S. Cutter

Theses and Dissertations

Interleukin-18 (IL-18) is a pro-inflammatory cytokine known to be involved in maintaining metabolic homeostasis; however, also capable of inducing cardiac dysfunction. Additionally, IL-18, has been shown to bind to a novel receptor, the Na-Cl Co-transporter (NCC). We hypothesized that NCC mediates IL-18 metabolic and cardiac signaling in mice. Using male C57BL/6J mice, we compared the metabolic and cardiac function changes after at least 8 weeks of high-saturated fat high sugar diet (Western Diet) in NCC knockout (NCCKO), IL-18 knockout (IL-18KO), and wild-type mice. We show that NCCKO mice have significantly increased body weight gain from baseline, no difference in fasting …

Advances In Dual-Energy Computed Tomography Imaging Of Radiological Properties, Dong Han

Theses and Dissertations

Dual-energy computed tomography (DECT) has shown great potential in the reduction of uncertainties of proton ranges and low energy photon cross section estimation used in radiation therapy planning. The work presented herein investigated three contributions for advancing DECT applications. 1) A linear and separable two-parameter DECT, the basis vector model (BVM) was used to estimate proton stopping power. Compared to other nonlinear two-parameter models in the literature, the BVM model shows a comparable accuracy achieved for typical human tissues. This model outperforms other nonlinear models in estimations of linear attenuation coefficients. This is the first study to clearly illustrate the …

Development And Validation Of A Semi-Physiological Pharmacokinetic (Pbpk) Model To Predict Systemic And Pulmonary Exposures After Intravenous, Oral Administration And Pulmonary Inhalation Of Selected Drugs, Budesonide, Tobramycin And Ciprofloxacin, In Humans, Bishoy Hanna

Theses and Dissertations

Using a semi-PBPK modeling/quantitative meta-analysis approach, this project investigated what factors affect pulmonary and systemic exposures of Budesonide (BUD), Tobramycin (TOB), and Ciprofloxacin (CIP) after inhalation:

Three structurally different pulmonary disposition models were developed for each drug, including pulmonary absorption (all three), excretion (TOB and CIP) and sequestration (TOB) in a peripheral and central lung compartment. Systemic disposition parameters were estimated using available human mean plasma (c_p(t)) and sputum (c_s(t)) concentration profiles after IV administration, and GI absorption parameters were estimated from these profiles after oral administration. Pulmonary disposition parameters were estimated from c_p(t) …

Understanding The Role Of Phosphoinositide 3-Kinase And Its Function As A Driving Force Behind The Er Stress Response In Fibrostenotic Crohn’S Disease-Affected Ileal Smooth Muscle Cells, Prashant Yadav

Theses and Dissertations

Crohn’s disease (CD) affects about 780,000 people in the United States alone, and it is estimated that 6-15 per 100,000 persons will receive a diagnosis of this disease each year. There currently is no cure for Crohn’s disease, and available medical therapies simply serve to alleviate the inflammation. This does not help treat fibrostenosis that Crohn’s disease patients may develop, which can only be treated surgically. Finding alternatives to treat CD requires an understanding of mechanisms at the biochemical level. In this thesis, we attempted to gain a better understanding of certain pathways found to be active in Crohn’s disease-affected …

Branched Short Chain Fatty Acid Isovaleric Acid Causes Smooth Muscle Relaxation Via Camp/Pka Pathway, Inhibits Gastrointestinal Motility, And Disrupts Peristaltic Movement, Bryan Adam Blakeney

Theses and Dissertations

Isovaleric Acid (IVA) is a 5-carbon branched chain fatty acid present in fermented foods and produced by the fermentation of leucine by colonic bacteria. IVA activates G-protein coupled receptors such as FFAR2, FFAR3, and OR51E1 known to be expressed on enteric neurons and enteroendocrine cells. We previously reported that the shorter, straight chain fatty acids acetate, propionate and butyrate, differentially affect colonic propulsion; however, the effect of branched chain fatty acids on gastrointestinal motility is unknown. We hypothesize that IVA relaxes smooth muscle in a cAMP/PKA dependent manner by direct action on smooth muscle cells. IVA will also decrease peristalsis …

Capacitive Memory Alters Alternans And Spontaneous Activity In A Minimal Cardiomyocyte Model, Tien Comlekoglu, Seth H. Weinberg

Biology and Medicine Through Mathematics Conference

No abstract provided.

High Performance Computation Of Cardiac Models In Real-Time Using Webgl, Abouzar Kaboudian, Flavio H. Fenton

Biology and Medicine Through Mathematics Conference

No abstract provided.

Uncertainty Of 1-D Fluid Models In Patients With Pulmonary Hypertension, Mitchel J. Colebank

Biology and Medicine Through Mathematics Conference

No abstract provided.

Multiple Blood-Brain Barrier Transport Mechanisms Limit Bumetanide Accumulation, And Therapeutic Potential, In The Mammalian Brain, Kerstin Römermann, Maren Fedrowitz, Philip Hampel, Edith Kaczmarek, Kathrin Töllner, Thomas Erker, Douglas H. Sweet, Wolfgang Löscher

Pharmacology and Toxicology Publications

There is accumulating evidence that bumetanide, which has been used over decades as a potent loop diuretic, also exerts effects on brain disorders, including autism, neonatal seizures, and epilepsy, which are not related to its effects on the kidney but rather mediated by inhibition of the neuronal Na-K-C1 cotransporter isoform NKCC1. However, following systemic administration, brain levels of bumetanide are typically below those needed to inhibit NKCC1, which critically limits its clinical use for treating brain disorders. Recently, active efflux transport at the blood-brain barrier (BBB) has been suggested as a process involved in the low brain:plasma ratio of bumetanide, …

Dynamical System Modeling To Simulate Donor T Cell Response To Whole Exome Sequencing-Derived Recipient Peptides: Understanding Randomness In Alloreactivity Incidence Following Stem Cell Transplantation, Vishal Koparde, Badar Abdul Razzaq, Tara Suntum, Roy Sabo, Allison Scalora, Myrna Serrano, Max Jameson-Lee, Charles Hall, David Kobulnicky, Nihar Sheth, Juliana Feltz, Daniel Contaifer, Dayanjan Wijesinghe, Jason Reed, Catherine Roberts, Rehan Qayyum, Gregory Buck, Michael Neale, Amir Toor

Massey Comprehensive Cancer Center Data

Quantitative relationship between the magnitude of variation in minor histocompatibility antigens (mHA) and graft versus host disease (GVHD) pathophysiology in stem cell transplant (SCT) donor-recipient pairs (DRP) is not established. In order to elucidate this relationship, whole exome sequencing (WES) was performed on 27 HLA matched related (MRD), & 50 unrelated donors (URD), to identify nonsynonymous single nucleotide polymorphisms (SNPs). An average 2,463 SNPs were identified in MRD, and 4,287 in URD DRP (p

The Role Of Menin-Mll Interaction In The Dissociation Between Cholestatic Liver Diseases And Cholangiocarcinoma, Laurent Ehrlich 2085637, Chad Hall Dr., Tori Sheppard, Julie Venter, April O'Brien, Terry C. Lairmore Dr., Gianfranco Alpini Dr., Shannon Glaser Dr.

Hepatobiliary Cancers: Pathobiology and Translational Advances

No abstract provided.

Hepatocellular Cancer Genome And Transcriptome Analysis Validates Clinically Significant Mutational Signatures With The Tgf-𝛃 Pathway, Shuyun Rao, Jian Chen, Kazufumi Ohshiro, Shoujun Gu, Sobia Zaidi, Wilma S. Jogunoori, Jon White, Nagarajan Pattabiraman, Raja Mazumder, Anelia Horvath, Ray-Chang Wu, Shulin Li, Chuxia Deng, Bibhuti Mishra, Rehan Akbanni, The Tcga Cancer Network, Lopa Mishra

Hepatobiliary Cancers: Pathobiology and Translational Advances

No abstract provided.

Proteomic Approach For Extracting Cytoplasmic Proteins From Streptococcus Sanguinis Using Mass Spectrometry, Fadi Elrami, Kristina Nelson, Ping Xu

Philips Institute for Oral Health Research Publications

Streptococcus sanguinis is a commensal and early colonizer of oral cavity as well as an opportunistic pathogen of infectious endocarditis. Extracting the soluble proteome of this bacterium provides deep insights about the physiological dynamic changes under different growth and stress conditions, thus defining “proteomic signatures” as targets for therapeutic intervention. In this protocol, we describe an experimentally verified approach to extract maximal cytoplasmic proteins from Streptococcus sanguinis SK36 strain. A combination of procedures was adopted that broke the thick cell wall barrier and minimized denaturation of the intracellular proteome, using optimized buffers and a sonication step. Extracted proteome was quantitated …

Rare Mutations And Potentially Damaging Missense Variants In Genes Encoding Fibrillar Collagens And Proteins Involved In Their Production Are Candidates For Risk For Preterm Premature Rupture Of Membranes, Bhavi P. Modi, Maria E. Teves, Laurel N. Pearson, Hardik I. Parikh, Piya Chaemsaithong, Nihar U. Sheth, Timothy P. York, Roberto Romero, Jerome F. Strauss

Human and Molecular Genetics Publications

Preterm premature rupture of membranes (PPROM) is the leading identifiable cause of preterm birth with ~ 40% of preterm births being associated with PPROM and occurs in 1% - 2% of all pregnancies. We hypothesized that multiple rare variants in fetal genes involved in extracellular matrix synthesis would associate with PPROM, based on the assumption that impaired elaboration of matrix proteins would reduce fetal membrane tensile strength, predisposing to unscheduled rupture. We performed whole exome sequencing (WES) on neonatal DNA derived from pregnancies complicated by PPROM (49 cases) and healthy term deliveries (20 controls) to identify candidate mutations/variants. Genotyping for …

Regulation Of Biliary Progenitor Cell Proliferation By Hedgehog Signaling In In Vivo And Ex Vivo Organoid Models, Nataliya Razumilava M.D., Junya Shiota M.D., Ramon Ocadiz-Ruiz Ph.D., Nureen Hanisah Mohamad Zaki, Kais Zakharia M.D., Michael Mathew Hayes, Juanita Lynn Merchant M.D., Ph.D.

Hepatobiliary Cancers: Pathobiology and Translational Advances

No abstract provided.

Targeting Hepatocellular Carcinoma Through Tgf-Β Pathway E3 Ligases, Kazufumi Ohshiro, Jian Chen, Shulin Li, Jon White, Asif Rashid, Lopa Mishra

Hepatobiliary Cancers: Pathobiology and Translational Advances

No abstract provided.

The Role Of Uridine-Cytidine Kinase 2 In The Development Of Hepatocellular Carcinoma, Dehai Wu, Song Tao, Keunsoo Ahn, Nicha Wongjarupong, Lewis Roberts

Hepatobiliary Cancers: Pathobiology and Translational Advances

No abstract provided.

Cca Development In The Background Of Congenital Hepatic Fibrosis/Caroli Disease, Eleanna Kaffe Mrs, Carlo Spirli, Luca Fabris, Massimiliano Cadamuro, Mario Strazzabosco

Hepatobiliary Cancers: Pathobiology and Translational Advances

No abstract provided.

Commonly Used H1 And H2 Histamine Receptor (Hr) Blockers Decrease Cholangiocarcinoma Xenograft Tumor Growth, Angiogenesis And Emt, Lindsey Kennedy, Laura Hargrove, Jennifer Demieville, Walker Karstens, Steven Smith, Heather Francis

Hepatobiliary Cancers: Pathobiology and Translational Advances

No abstract provided.

Signaling Components Involved In The Hormone Induced Translocation Of Enac In Cultured Adult Human Fungiform (Hbo) Taste Cells, Deanna Hojati

Theses and Dissertations

The amiloride-sensitive epithelial Na⁺ channel, ENaC, is the Na⁺-specific salt taste receptor in rodents. Compared to rodents, human salt taste perception is amiloride-insensitive. In rodents the ENaC is composed of aβg-subunits. Whereas humans express an additional subunit, the d-ENaC subunit. ENaC in human taste cells is composed of aβg-subunits or dβg-subunits, with the latter being amiloride-insensitive. Currently, it is not known if dβg-ENaC expression and trafficking is regulated by hormones and their downstream intracellular signaling effectors. The aim of this study is to investigate if arginine vasopressin (AVP), aldosterone, and cAMP regulate d-ENaC expression and trafficking in …

Thyroid Hormone As A Method Of Reducing Damage To Donor Hearts After Circulatory Arrest, William P. Adams

Theses and Dissertations

There is a chronic lack of donor hearts to meet the need for heart transplant both in the US and worldwide. Further, the use of available hearts is limited by the short period between collection and implantation during which the heart can be safely preserved ex vivo. Using mid-thermic Langendorff machine perfusion, we have been able to preserve the metabolic function of a healthy heart for up to 8 hours, twice the limit for current static cold storage. We have also been able to preserve the metabolic function of a damaged DCD Heart collected 30 minutes after cardiac arrest …

Epigenetic Editing To Validate Findings From Methylome-Wide Association Studies Of Neuropsychiatric Disorders, Robin F. Chan

Theses and Dissertations

DNA methylation is necessary for learning, memory consolidation and has been implicated in a number of neuropsychiatric disorders. Obtaining high quality and comprehensive data for the three common forms of methylation in brain is challenging for methylome-wide association studies (MWAS). To address this we optimized a panel of enrichment methods for screening the brain methylome. Results show that these enrichment techniques approach the coverage and fidelity of the current gold standard bisulfite based techniques. Our MBD-based method can also be used with low amounts of genomic material from limited human biomaterials. Psychiatric disorders have high prevalence and are often chronic …

Role Of Translation Initiation In Regulation Of Epithelial Junctions And Cell Motility, Fahda Fawaz Alsharief

Theses and Dissertations

The integrity and barrier properties of intestinal epithelium are determined by specialized adhesive structures known as intercellular junctions; composed of adherens junctions (AJs), tight junctions (TJs) and focal adhesions that mediate cell-cell and cell matrix interactions, respectively. These two types of epithelial cell adhesions regulate each other during disruption and restitution of the epithelial barrier. Inflammatory cytokines such as interferon gamma (IFNγ) and tumor necrosis factor alpha (TNFα) are elevated during intestinal inflammation. The most notable effects of IFNγ and TNFα on intestinal epithelial homeostasis involve disruption of apical junctions and attenuation of cell migration. Although molecular mechanisms underlying these …

Short And Long Chain Free Fatty Acids Differentially Regulate Glucagon-Like Peptide-1 And Peptide Yy Transcript Levels In Enteroendocrine Cells (Stc-1), Colin M. Catherman

Theses and Dissertations

The regulation of glucagon-like peptide-1 and peptide YY hormone levels are regulated based on different influential factors, but primarily levels are dependent upon ingested food content. As meals today become more fat-enriched, there is greater requirement for evaluation of these hormones that regulate insulin and satiety levels within the body. We have shown that the gene expression transcript production of glucagon-like peptide-1 and peptide YY are modulated by different concentrations, and times of short-chain fatty acids and long-chain fatty acids. Although the peptide hormone levels have the influential physiological role on effector tissue, the regulation of these hormones begins at …

Tissue Factor Expression, Regulation, And Signaling In Human Airway Cells, Michael D. Davis

Theses and Dissertations

Rationale: Tissue Factor (TF) is a transmembrane glycoprotein that canonically functions as the initiator of the coagulation cascade. Increased levels of TF have been associated with inflammatory airway diseases. Since lipopolysaccharide (LPS) is known to elicit and inflammatory response in airway epithelium, we hypothesized that airway epithelial cells release TF when exposed to LPS. Since TF aids in local wound healing, we also hypothesized that inhibition of TF would decrease NHBE growth. The specific aim of this work was to evaluate the effects of LPS exposure on TF production and release from airway epithelia and determine the signaling pathways involved. …

Sleep Disturbances And Depression: The Role Of Genes And Trauma, Mackenzie J. Lind

Theses and Dissertations

Sleep disturbances and insomnia are prevalent, with around 33% of adults indicating that they experience at least one main symptom of insomnia, and bidirectional relationships exist with common psychopathology, particularly major depressive disorder (MDD). However, genetic and environmental (e.g., traumatic event exposure) contributions to the etiology of these phenotypes are not yet well understood. A genetically informative sample of approximately 12,000 Han Chinese women aged 30-60 (50% with recurrent MDD) was used to address several gaps within the sleep literature. Sleep disturbances were assessed in all individuals using a general item addressing sleeplessness (GS). A sleep within depression sum score …