Medicine and Health Sciences Commons^™

Cholesterol Regulation Of Pulmonary Endothelial Calcium Entry Following Chronic Hypoxia, Bojun Zhang

Biomedical Sciences ETDs

Chronic hypoxia (CH)-induced pulmonary hypertension (PH) is associated with diminished ATP-induced endothelial Ca2+ entry as well as membrane cholesterol in pulmonary arteries. Store-operated Ca2+ entry (SOCE) and depolarization-induced Ca2+ entry are major components of the response to ATP and are similarly decreased after CH. Because endothelium-dependent vasodilation is closely associated with pulmonary endothelial [Ca2+]i, the blunted agonist-induced Ca2+ influx in pulmonary artery endothelial cells (PAEC) may contribute to the development of CH-induced PH. Interestingly, impaired agonist-induced Ca2+ influx in PAEC following CH can be restored by membrane cholesterol supplementation. In the current studies, we hypothesized that impaired Ca2+ entry in …

Post-Transcriptional Regulation Of Addiction-Related Behaviors: Opposing Roles Of Nucleus Accumbens Mir-495 And Hud, Robert J. Oliver Jr

Biomedical Sciences ETDs

Substance use Disorders (SUDs) are characterized by chronic relapse after periods without symptoms. This has been hypothesized to stem from persistent alterations in corticolimbic circuit function and structure caused by drug-induced alterations in addiction-related gene (ARG) expression. Transcriptional and epigenetic regulation of ARGs and addiction-like behaviors have been well characterized but the role of post-transcriptional regulation is an understudied, yet promising field. RNA binding proteins (RBPs) are one post-transcriptional regulator of mRNA stability. HuD is a neuronal specific RBP that stabilizes mRNAs and is regulated by neuronal activity and cocaine. Another type of post-transcriptional regulator, microRNAs (miRNAs), are non-coding RNAs …

Patient Centered Family Planning Care, Lauren Thaxton Md, Mba

Biomedical Sciences ETDs

The Institute of Medicine defines six important domains of health care quality: safety, efficacy, timeliness, efficiency, equitable delivery and patient-centeredness. Quality family planning care aims to provide individuals with the tools needed to engage in healthy and satisfying sex lives while planning and spacing pregnancies to achieve desired family size. The field of family planning strongly relies on the domain of patient-centeredness as individual values and preferences guide clinical care. Yet large gaps in knowledge exist in understanding how to improve patients’ clinical experience. This hybrid thesis posits avenues for improving the quality and patient-centeredness of clinical care.

Quality care …

Exploring Biological Heterogeneity And Its Consequences At Tissue And Cellular Scales Through Mathematical And Computational Modeling, Romica Kerketta

Biomedical Sciences ETDs

This dissertation explores the effects of heterogeneity across different biological scales in cancer as well as normal cells. At the tissue scale, we investigated the variability present in the tumor microenvironment and its effect on patient chemotherapeutic outcomes using a mathematical model of drug transport. We found that parameters such as tumor blood perfusion and radius of blood vessel had an impact on the tumor cytotoxicity. This indicated that the physical microenvironment of the tumor is an important regulator of the tumor response to chemotherapy. At the cellular scale, we investigated the heterogeneity present on the membrane landscape of ErbB2 …

Photography And Catalogue Of Cutaneous Vascular Malformations Of Patients With Ccm1- Chm Cerebral Cavernous Malformations, Athanasios K. Manole

Biomedical Sciences ETDs

Due to a genetic mutation, a rare and potentially fatal disease has spread throughout New Mexico. This disease, Familial Cerebral Cavernous Malformation (FCCM1-CHM), is due to a mutation that affects peoples of Hispanic heritage in New Mexico. The FCCM disease is characterized by the development of dilated, thin walled, leaky vessels that occur in the brain and spinal cord. As a result of this genetic mutation, the lesions in the blood vessels of the brain and spinal cord are highly susceptible to hemorrhaging into surrounding tissue. This can lead to headaches, seizure, and possibly death. Researchers at the University of …

Mk2 Promotes Colorectal Cancer Development, Invasion, And Growth Through Mk2-Induced Cytokines, Anita Lynne Ray

Biomedical Sciences ETDs

Colorectal cancer (CRC) is the third most common malignancy in the United States for men and women. A major risk factor for CRC development and progression is inflammation, in particular the inflammatory cytokines IL-1, IL-6, and TNF-α. These proteins promote critical cancer functions, such as proliferation, invasion, survival, and migration. Control of inflammation is one potential area of therapeutic intervention for some cancers. Because signaling of these cytokines overlaps in many of the same pathways, targets upstream of protein production could prove an effective strategy to reduce inflammation. MAPK-activated protein kinase 2 (MK2) pathway controls production of these cytokines within …

Relationship Between Weight Status, Demographic Variables And Health-Related Quality Of Life In New Mexico Adolescents, Ukeme Umoh

Biomedical Sciences ETDs

This study evaluated the relationship between weight status, demographic variables and HRQOL in New Mexico adolescents. This secondary analysis uses baseline data from 991 adolescents in the 9^th and 10^th grades enrolled in the ACTION PAC clinical trial. HRQOL was assessed using the validated Pediatric Quality of Life Inventory Version 4.0 (PedsQL 4.0). Body mass index (BMI) percentiles were calculated from anthropometric measurements, and demographic variables (age, sex, race/ethnicity and household income) were obtained via self-report. Obese adolescents (BMI ≥ 95^th percentile) had lower total (pthpercentile) adolescents. Males reported higher total (p

Barriers To Treatment With Buprenorphine For Opioid Addiction In New Mexico, Kanwal Qidwai

Biomedical Sciences ETDs

More persons died from drug overdoses in the United States since 2000 than during any past years on record. There were approximately one and a half times more drug overdose deaths in the United States than deaths from motor vehicle crashes in 2015. Opioids, primarily prescription pain relievers and heroin, are the main drugs associated with overdose deaths. The 2014 data demonstrates that the United States opioid overdose epidemic includes two distinct but interrelated trends: a 15-year increase in overdose deaths involving prescription opioid pain relievers along with a recent rise in illicit opioid overdose deaths, driven by heroin. Natural …

Cortico-Striatal Coordination Disrupted In Behaviorally Inflexible Moderate Prenatal Alcohol Exposed Mice, Kristin L. Marquardt

Biomedical Sciences ETDs

Up to 61% of adolescent school aged children with fetal alcohol spectrum disorder (FASD) have been suspended or expelled. Executive function deficits, like dis-inhibition and cognitive inflexibility, have been proposed to be better predictors of behavioral problems then IQ score, which qualifies these individuals for developmental disability and special school programs. Reversal learning, a widely used behavioral paradigm for assessing cognitive flexibility across species, has been shown to be impaired in rodent models of prenatal alcohol exposure (PAE). Here we show that a mouse model with daily maternal drinking, resulting in a BAC of 85 mg/dl throughout gestation, results in …

Detection Of Healthcare-Associated Infectious Disease Outbreaks With A Special Look At Clostridium Difficile Infection In Long-Term Care Facilities, Almea Matanock

Biomedical Sciences ETDs

Healthcare-associated infections (HAI) are a major cause of morbidity and mortality and a public health priority. However, standard procedures and comprehensive guidelines for HAI outbreak detection and response are still needed. This hybrid thesis describes what is known about HAI outbreaks in the introduction, reviews the HAI outbreaks reported to New Mexico Department of Health (NMDOH), in the first paper, and then in the second paper examines how established methods for detecting infectious disease outbreaks perform in identifying Clostridium difficile infection (CDI) outbreaks in long-term care facilities (LTCF) in Bernalillo County, New Mexico, and finally, it closes with our overall …

Identification & Evaluation Of Dna Ligase Inhibitors: Predicting The Binding Of Small Molecules To The Dna Binding Domain By Molecular Modeling, Timothy Rl Howes

Biomedical Sciences ETDs

The phosphodiester backbone of DNA is maintained by DNA ligases. In human cells, there are three genes that encode DNA ligase polypeptides with distinct but overlapping functions. A series of small molecule inhibitors of human DNA ligases were previously identified using a rational structure-based approach. Three of these inhibitors, L82, a DNA ligase I selective inhibitor, and L67, an inhibitor of DNA ligases I and III, and L189, an inhibitor of all three human DNA ligases, have related structures. Here I present and characterize L82-G17 a next-generation ligase I specific inhibitor. L82-G17 is a potent ligase I uncompetitive inhibitor that …

Cd82 Membrane Scaffolding Regulates Hematopoietic Cell Functions, Christina M. Termini

Biomedical Sciences ETDs

Through their ability to self-renew and differentiate, hematopoietic stem/progenitor cells (HSPCs) maintain the adult blood and immune systems. The microenvironment, or niche, in which HSPCs reside, serves as a critical regulator of HSPC functions. As previous work has identified the tetraspanin CD82 as a mediator of HSPC-niche interactions, we aimed to determine the mechanism by which this occurs. Our data demonstrate that CD82 expression and scaffolding regulate HSPC interactions with niche components by organizing the α4 integrin subunit into tightly packed nanoclusters. The HSPC niche can also protect acute myeloid leukemia (AML) cells from therapeutics. Therefore, we next examined how …

Developing Fluorogen Activating Protein-Fluorescent Protein Fret Pairs For Live Cell Imaging, Genevieve Kate Phillips

Biomedical Sciences ETDs

Fluorogen activating proteins (FAPs) are genetically encoded tags made from single chain antibody fragments (scFv) designed to bind fluorogens with high specificity. Both the fluorogen and FAP can be modified to provide flexibility in properties such as affinity, membrane permeability, spectra, and quantum yield. The fluorogen Malachite Green (MG) has two excitation peaks, the maximum at 630 nm and a secondary peak at 450 nm. The emission spectra of blue-emitting fluorescence proteins, such as mCerulean (mCer), overlap with the MG secondary peak, generating a FRET pair with large Stokes shift emission. Using 405 nm excitation of mCer, we observe acceptor …

Adenosine Receptor Activation In Spreading Depolarization And Ischemic Injury, Britta E. Lindquist

Biomedical Sciences ETDs

Spreading depolarization (SD) is a propagating wave of neuronal activation occurring in the central nervous system. SD is accompanied by depression of synaptic activity and complex blood flow changes. Better understanding the mechanisms underlying these phenomena may be important to elucidate the pathophysiology of human disease, and to develop therapeutic interventions. SD contributes significantly to the morbidity and mortality of thromboembolic and ischemic stroke, subarachnoid hemorrhage, and traumatic brain injury. Experiments described in this dissertation were designed to investigate the regulation of neuronal and vascular physiology during spreading ii depolarization and its aftermath. The overall goal of these studies was …

Validation Of The Pre-B Cell Receptor As A Therapeutic Target In B Cell Precursor Acute Lymphoblastic Leukemia, Michael F. Erasmus

Biomedical Sciences ETDs

This dissertation is built upon the fundamental idea that the pre-B cell receptor (pre-BCR) is important to leukemia cell survival and a logical therapeutic target in B cell precursor acute lymphoblastic leukemia (BCP-ALL). The pre-BCR is expressed early at a specific stage during B cell development where it plays a central role in survival of healthy B lymphocytes. This receptor is composed of the membrane heavy chain (mIgμ) associated with surrogate light chain components, 5 and VpreB. Through the use of advanced imaging modalities, in particular two-color single particle tracking (SPT), we showed that pre-BCRs formed transient, homotypic interactions. These …