Life Sciences Commons^™

A Novel Exo-Proteomic Approach To The Study Of Traumatic Brain Injury, Ron B. Moyron

Loma Linda University Electronic Theses, Dissertations & Projects

Concussions and Traumatic Brain Injuries (TBI) are significant health concerns and affect a wide cross section of society. Current diagnostic criteria and modalities, such as brain imaging and subjective measures of consciousness such as the Glasgow Coma Scale (GCS) score, are insufficient to properly diagnose the full spectrum of head injuries. Assessment of injury severity and outcome are further complicated by the vast array of symptoms, many of which mimic those displayed by other disorders. It is important to possess a better diagnostic tool for head injury triage and outcome prediction. One current line of inquiry seeks to discover a …

Rna-Seq Reveals Transcriptomic Program Associated With Stemness In Taxane Resistant Prostate Cancer, Christina K. Cajigas-Du Ross

Loma Linda University Electronic Theses, Dissertations & Projects

There is no cure for advanced prostate cancer (PCa), and taxane chemotherapy is the only treatment option once other therapies have failed. However, this is problematic since all patients eventually develop chemoresistance. Emerging treatments for advanced PCa have shown promise at the benchside, but clinical trials have not resulted in newly approved drugs due in part to redundant survival pathways utilized by prostate tumor cells to maintain therapy-resistance. Using RNAsequencing—an innovative approach for quantifying gene expression changes—this dissertation sought to elucidate chemoresistance-associated molecular pathways as a catalyst to develop new therapeutic targets. Results revealed a differential upregulation of stemness-associated genes …

Effects Of Omega-3s And Vitamin E Prophylactic Diets And The Implications Of Lipid Transport In Spinal Cord Injury, Kathia Cordero-Caban

Loma Linda University Electronic Theses, Dissertations & Projects

Traumatic injury to the central nervous system (CNS) presents a devastating problem to our society. Although current interventions are promising, no effective treatments are available. The neural membrane fatty acid composition is markedly altered during the first few days after spinal cord injury (SCI). SCI results in autonomic dysfunction, paralysis, spasticity, and significant chronic neuropathic pain. The trauma leads to significantly increased levels of free radical and oxidative stress that contribute to obstructing tissue healing and recovery. A growing body of evidence shows that administration of hydrophobic molecules such as Vitamin E and long-chain omega-3 polyunsaturated fatty acids (ω3PUFAs) are …

Effect Of Extracellular Survivin And Lymphoma Exosomes On Natural Killer Cells, Heather R. Ferguson Bennit

Loma Linda University Electronic Theses, Dissertations & Projects

Tumors alter their microenvironment to promote survival using methods such as angiogenesis promotion, growth signals, and immune suppression. The immune system becomes unresponsive to transformed neoplastic cells through a variety of methods including T cell suppression, increased myeloid-derived suppressor cells (MDSCs), and reduced natural killer (NK) cell activity. NK cells have inherent killing capabilities and thus are among the first responders in recognizing and destroying abnormal cells. However, many types of cancers inhibit the surveillance and cytotoxic abilities of NK cells by releasing exosomes, vesicles that can modulate the tumor microenvironment (TME) and intercellular communication for the purpose of enhancing …

Prenatal Undernutrition, Metyrapone, And The Cerebrovasculature, Lara Durrant

Loma Linda University Electronic Theses, Dissertations & Projects

The link between intrauterine environmental conditions and adult cardiovascular system is well established. Independent of lifestyle factors such as poor diet and exercise habits, individuals who have been exposed to stressful conditions in utero show an increased risk of health problems such as hypertension, stroke, and type II diabetes. In support of the Fetal Origin of Adult Disease hypothesis, many labs have reported permanent anatomical and physiological changes associated with fetal stress and nutrient deficiency, with a focus on organ systems such as the kidney and heart. One key idea proposed by many of these studies is the glucocorticoid hypothesis, …

A Novel Population Of Cardiovascular Progenitors Persist In Neonates As Mesendodermal Cells, Julia Kim

Loma Linda University Electronic Theses, Dissertations & Projects

The rise in mortality due to cardiovascular disease has increased the need to develop an efficient regenerative therapeutic for heart failure. Numerous cell-based therapies have been investigated for myocardial regeneration; however, an optimal progenitor has yet to be discovered. Identifying a resident cell population with enhanced ability to differentiate into multiple lineages would greatly contribute to the field of stem cell-based regenerative therapy. Evidence suggests that endogenous cardiovascular progenitor cells (CPCs) that have been isolated from the heart itself express ISL1, KDR, and MESP1, and are capable of differentiating into all major cardiac lineages. The earlier developmental stage at which …

Pas Signaling Mechanisms In Aer And Aer2, Darysbel Garcia

Loma Linda University Electronic Theses, Dissertations & Projects

PAS domains are widespread signal sensors that share a conserved three-dimensional αβ fold that consists of a central β-sheet flanked by several α- helices. The aerotaxis receptor Aer from Escherichia coli and the Aer2 chemoreceptor from Pseudomonas aeruginosa both contain PAS domains. Aer senses oxygen (O2) indirectly via an FAD cofactor bound to its PAS domain, while Aer2 directly binds O2 to its PAS b-type heme cofactor. The Aer and Aer2 PAS domains both interact with a signal transduction domain known as a HAMP domain. The PAS-HAMP arrangement differs between Aer and Aer2, with Aer- PAS residing adjacent to its …

Proteomic Profiling Of Serum Derived Exosomes From Prostate Cancer Patients, David Turay

Loma Linda University Electronic Theses, Dissertations & Projects

Touted among the major achievements in the diagnosis and management of Prostate cancer (PCa) in the past few decades has been, the dramatic decline of men with advanced/metastatic PCa at diagnosis coupled with a significant improvement ( >90%) in the five and ten year survival rates of the disease. Non-palpable PCa (potentially clinically treatable disease) now accounts for 70-80% of all newly diagnosed cases of PCa. Preceding these changes by about a decade was the introduction of Prostatic Specific Antigen (PSA) into clinical practice; first as biomarker for monitoring response to therapy and subsequently as a complementary screening tool. It …

Mechanism Of Chimeric Vaccine Mediated Immune Suppression Of Human Dendritic Cells, Jacques Christian Mbongue

Loma Linda University Electronic Theses, Dissertations & Projects

Type 1 diabetes mellitus is a chronic inflammatory disease in which insulin producing β-cells of the pancreatic islets are killed by autoreactive cells of the immune system in response to a loss of tolerance. Dendritic cells (DC) interact predominantly with naïve T cells to regulate the delicate balance between immunity and tolerance required to maintain immunological homeostasis. In this dissertation, immature human dendritic cells (iDC) were inoculated with a chimeric fusion protein vaccine containing the pancreatic β-cell auto-antigen proinsulin linked to a mucosal adjuvant the cholera toxin B subunit (CTB-INS). Proteomic analysis of vaccine inoculated DCs revealed strong up-regulation of …

Comparative Studies Of Tslp And Il-7 In Normal Early Human Neonatal And Adult B Cell Development, Terry-Ann Milford

Loma Linda University Electronic Theses, Dissertations & Projects

Defining the role of cytokines in promoting human B cell development is important for understanding B cell leukemia and for developing strategies to restore B cell production that is lost during some therapies. The purpose of this study was to investigate the roles of the IL-7R ligands, thymic stromal lymphopoietin (TSLP) and IL- 7, in the early stages of normal postnatal and adult human B cell development. Using novel in vitro and in vivo model systems, we show that TSLP and IL-7 are able to expand B cell precursors individually and in combination from CB hematopoietic stem cells. In this …

Crotalus Snake Venom Preconditioning To Prevent Surgical Brain Injury, Cherine Hee-Sun Kim

Loma Linda University Electronic Theses, Dissertations & Projects

Preventive measures are increasingly relevant to medical practice. Preconditioning, a preemptive therapy that administers mildly harmful stimuli to induce endogenous protective mechanisms before major injury, has been shown to minimize injury in many animal models. Given the elective nature of most neurosurgical procedures, the surgical brain injury (SBI) rodent model provides an ideal platform for preconditioning. Our work shows that preconditioning with Crotalus rattlesnake venom, known for its hemorrhagic and inflammatory effects, mitigates some harmful effects of SBI. We have identified two proteins of interest in Crotalus venom: snake venom metalloproteinase (SVMP), an enzyme with hemorrhagic effects, and phospholipase A2 …

Curcumin: A Multi-Dimensional Approach To Pancreatic Cancer Targeting Cell Death And Exosomes, Carlos J. Diaz Osterman

Loma Linda University Electronic Theses, Dissertations & Projects

Pancreatic cancer is currently one of the most difficult diseases to treat due to difficulty of detection and the aggressive nature of the disease. In addition, pancreatic cancer has the highest mortality rates compared to other cancer types. These mortality rates are attributable in part to increasing resistance to cancer therapy. Cancer therapy resistance is caused by adaptations that favor survival within cancer cells and their environment, termed the tumor microenvironment. Intracellular adaptations include the overexpression of resistance-linked genes, such as the inhibitor of apoptosis (IAP) family of proteins and overall resistance to cell death. Adaptations in the tumor microenvironment …

Modulation Of T Lymphocytes By Tumor-Released Survivin, Jessica Marie Jutzy

Loma Linda University Electronic Theses, Dissertations & Projects

The tumor microenvironment is an area of intense interaction between normal and malignant cells. Factors and cell types within this environment can play a crucial role in the progression or regression of the tumor. Of primary interest are tumor-infiltrating T lymphocytes, which have been shown to have a key role in modifying the dynamics of the tumor microenvironment to promote or prevent tumor growth. While there is much in vitro and in vivo evidence for a modification of the tumor infiltrating T cell population toward a pro-tumor environment, what induces these changes within the tumor microenvironment has remained elusive. Our …

Retinoic Acid Regulation Of Thyroid Hormone Action In Bone Cells, Anjali Babbar

Loma Linda University Electronic Theses, Dissertations & Projects

Retinoic acid and thyroid hormone are known to play key roles in the regulation of endochondral ossification. However, the issue of whether these two hormones interact with each other to regulate bone functions remains to be established. We investigated how thyroid hormone and retinoic acid interact to regulate cells involved in endochondral bone formation. We demonstrate that thyroid hormone treatment stimulates differentiation of ATDC5 chondrocytes and promotes formation of mineralized nodules while retinoic acid treatment at high dose inhibits chondrocyte differentiation and formation of mineralized nodules. Furthermore, thyroid hormone induced mineralized nodule formation is inhibited by co-treatment with retinoic acid …

Survivin: Regulation By Yy1 And Role In Pancreatic Cancer Combination Therapy, Nicholas R. Galloway

Loma Linda University Electronic Theses, Dissertations & Projects

Despite significant clinical and basic science advancements, cancer remains a devastating disease that affects people of all ages, races, and background. Survivin, the fourth most common transcript found in cancer cells, is a protein that is thought to be involved in the enhanced proliferation, survival, and metastasis of cancer cells. Therefore understanding how this gene is regulated is potentially of vital importance to improving cancer management and therapy. Our work has identified a novel transcriptional regulator of survivin called Yin Yang 1 (YY1). YY1 is a transcription factor that has been observed to activate some gene promoters and repress others, …

Expression And Function Of Ca2+-Activated K+ Channels In Uterine Arteries, Ronghui Zhu

Loma Linda University Electronic Theses, Dissertations & Projects

Chronic hypoxia during pregnancy is one of the most common insults to the maternal cardiovascular system and fetal development, and is associated with increased uterine vascular tone and heightened risk of preeclampsia and fetal intrauterine growth restriction (IUGR). The present study tested the hypothesis that calcium-activated potassium (KCa) channels play an essential role in uterine vascular adaptation to pregnancy, which is inhibited by chronic hypoxia during gestation. Uterine arteries (UAs) were isolated from nonpregnant ewes (NPUAs) and near-term pregnant ewes (PUAs) that had been maintained at sea level (~300 m) or exposed to high altitude (3,801 m) for 110 days. …

Caveolins And Njks Influence Brain Endothelial Permeability After Juvenile Tbi, David Olufemi Ajao

Loma Linda University Electronic Theses, Dissertations & Projects

Disruption of blood-brain barrier (BBB) is a key secondary event that exacerbates brain damage following traumatic brain injury (TBI). BBB disruption is particularly damaging to the developing brain – which is highly vulnerable to various stress stimuli, resulting in increased brain swelling, disrupted cerebral blood flow (CBF) autoregulation, long-term disabilities and death following TBI in young demographic. Unsurprisingly, BBB disruption and the resultant cerebral edema have emerged as therapeutic targets in juvenile TBI. It is therefore important to understand the molecular players and mechanisms involved in TBI-induced BBB disruption in the juvenile brain. To this end, the endothelial caveolins and …

Small Molecule Inhibitors Of Hpv16 E6, Chung-Hsiang Yuan

Loma Linda University Electronic Theses, Dissertations & Projects

High-risk human papillomaviruses (HR-HPVs) cause nearly all cases of cervical cancer. HPV 16 E6, one of two viral oncogenes, protects cells from apoptosis by binding to and accelerating the degradation of several apoptotic proteins, including caspase 8 and p53. We proposed that blocking the interactions between HPV E6 and its partners using small molecules had the potential to re-sensitize HPV+ cells to apoptosis. To test this prediction, we screened libraries of small molecules for candidates that could block E6/caspase 8 binding, and identified several candidates from different chemical classes. Testing hits for dose-dependency and specificity in vitro and for toxicity …

Aging And Sympathetic Neurotransmission In Two Strains Of Rats That Differ In Longevity And Immune Profiles, Sam David Perez

Loma Linda University Electronic Theses, Dissertations & Projects

Age-related changes in sympathetic neurotransmission in immune organs may be associated with immunosenescence; however no causal relationship has been established. From previous studies in Fischer rats (F344), we have found that during middle age, sympathetic nerve activity (SNA) rises in the spleen followed by a decline in noradrenergic (NA) innervation. Also, increased sympathetic signaling via betaadrenergic receptor (β-AR) and reduced proliferation of lymphocytes are evident with increasing age. Although SNA progressively rises with age, effects of age on sympathetic factors may be different across rat strains. If causal relationships exist between sympathetic activity and immune function, they may be related …

Ricin B Chain-Insulin Fusion Protein Immunomodulation Of Type 1 Diabetes, James Edward Carter Iii

Loma Linda University Electronic Theses, Dissertations & Projects

Type 1 diabetes mellitus (T1D) is a debilitating chronic inflammatory disease of the insulin-producing pancreatic islet β-cells that results from a combination of genetic and environmental factors. Attempts to suppress Th1-mediated autoimmune diseases such as T1D by mucosal delivery of autoantigens for immunotolerization have yielded only partial success. Attainment of satisfactory levels of sustained immunological tolerance remains to be accomplished. To restore self-tolerance requires delivery of sufficient amounts of autoantigen to stimulate regulatory T helper cells that function to survey the gut and induce tolerance to consumed antigens such as food. Oral delivery of autoantigens has previously been shown to …

Postprandial Effects Of Pecans Ingestion On Plasma Level Of Nutrients, Polyphenolic Compounds And Biomarkers Of Antioxidant Status In Human Volunteers, Chatrapa Hudthagosol

Loma Linda University Electronic Theses, Dissertations & Projects

Pecans (Carya illinoinensis) are rich sources of polyphenolic compounds and nutrients, which have antioxidant capacity results in favorable reductions in plasma lipids and lipoproteins. However, the health benefits of pecans may not be limited to blood lipid changes. There has been very little investigation into the contribution of bioactive components found in nuts to antioxidant protection. The purposes of the study were 1) to determine the impact of pecan consumption on concentration of total plasma polyphenols and their peak concentration over time. 2) to measure the effect of a pecan diet on postprandial levels of plasma lipid peroxidation …

Anti-Inflammatory Effects Of Ppar-Gamma In Surgical Brain Injury (Sbi), Amy Hyong

Loma Linda University Electronic Theses, Dissertations & Projects

Introduction: Brain injury can be caused by neurosurgical procedures themselves, due to direct trauma, retractor stretch, intraoperative hemorrhage and electrocautery damage. As a result of this surgical brain injury (SBI) postoperative complications such as inflammation, brain edema, and cell death can occur in the susceptible brain areas. Cerebral inflammation is a known contributor to the pathophysiology of brain injury. Following brain injury, the release of inflammatory mediators facilitates the development of BBB breakdown, cerebral edema, oxidative stress and neuronal death, resulting in further tissue damage in the brain and poor neurological outcomes. This study evaluates whether the use of a …

Novel Binding Domains Mediate Binding Of Hpv 16 E6 To Fadd And Procaspase 8, Sandy S. Tungteakkhun

Loma Linda University Electronic Theses, Dissertations & Projects

To evade the host response to infection, viruses have developed means to survive and propagate. HPV 16, a causative agent of cervical cancer and of some cases of oropharyngeal cancers, is one example. We have reported that the early viral protein E6 binds to proteins necessary for propagation of the apoptotic signal following receptor/ligand interactions, such as those mediated by FADD DED and procaspase 8 DED. E6 expression leads to the dose-dependent accelerated degradation of FADD and the protection of E6-expressing cells from Fas-induced apoptosis. Surprisingly, the splice isoforms of E6, E6_large and E6*, affect the stability of procaspase …

Mechanisms Of T Helper Cell Modulation In A Simulated Space Radiation Environment, Asma Rizvi

Loma Linda University Electronic Theses, Dissertations & Projects

Exposure to solar particle events (SPEs) poses the most serious threat to astronaut health. Due to this radiation environment, exploration of the solar system beyond Earth’s orbit entails many risks for the crew on these deep space missions. Depression or dysfunction of the immune system is a major concern due to its high radio-sensitivity; potential consequences include overwhelming infection, development of cancer, fibrosis, and poor wound healing. Astronauts are also exposed to low dose/low dose rate (LDR) radiation. A three month stay at the international space station exposes them to ~ 0.05 Gy of radiation.

C57BL/6 mice received LDR gamma-radiation …

Response Of Endothelial Cells To Stressors: The Impact Of Aging And Diabetes, Katie Mclellan

Loma Linda University Electronic Theses, Dissertations & Projects

Preliminary research indicates there is some impairment of the endothelial cells to respond to single stressors such as local heat, shear stress, and global heat in older people and people who have diabetes. The response of the skin blood flow to local heat is an indicator of the endothelial cells ability to cope with stress. In addition, factors such as thicker subcutaneous fat and skin moisture may impair the skin’s ability to dissipate heat. For older people and people with diabetes, this endothelial dysfunction may cause an even more diminished response to multiple stressors. However, no studies have examined the …

Radiation-Induced Glutamate Transport Alterations In Neuron-Astrocyte Coupling, Martha Celia Sanchez

Loma Linda University Electronic Theses, Dissertations & Projects

Exposure of the central nervous system (CNS) to ionizing radiation is known to result in behavioral, cognitive, and motor deficits - effects similar to those seen in many neurodegenerative disorders. Neurons and astrocytes, two principal cell types in the brain, coexist as an interdependent metabolic unit via the neurotransmitter glutamate. Disruption of this metabolic coupling would have widespread effects within the CNS, therefore it is hypothesized that ionizing radiation impairs glutamate transport and metabolism, and increases oxidative stress, ultimately impairing neuron-astrocyte coupling. We propose to investigate the mechanism and determine the impetus for radiation-induced neurotoxicity by measuring the temporal sequence …

The Role Of Nogo-A During Development Of The Chick Central Nervous System, Shelly A. Caltharp

Loma Linda University Electronic Theses, Dissertations & Projects

Nogo-A is a potent inhibitor of axon regeneration that is expressed by myelin forming oligodendrocytes of the adult central nervous system (CNS). However, neuronal expression of Nogo-A during development suggests an additional role. Little is known about the putative functions of Nogo-A during embryonic development. To examine its potential role we isolated and analyzed the Nogo-A sequence in the chick, we localized its mRNA expression pattern and cell-specific distribution during key phases of cortical development, and studied regulation of its expression during phases that showed promise of function based on expression patterns.

Our results revealed five previously undescribed Nogo-A specific …

Electromagnetic Differences In The Brain During Memory Retrieval, Warren Scott Merrifield

Loma Linda University Electronic Theses, Dissertations & Projects

The primary objectives for this experiment were to analyze the neuroanatomical correlates of autobiographical, episodic and semantic memory, use a different paradigm to promote episodic memory retrieval, and employ a different analysis technique to understand retrieval processes. Autobiographical and episodic memories are personal memories from the past. Autobiographical is more general (e.g. a street name of a house growing up) and episodic is more specific to time (e.g. 13th birthday party that took place on a street). For autobiographical and episodic memory retrieval operations, there is no general consensus as to the localization of function, but bilateral activation of the …

Iron Dysregulation And Inflammation In Alzheimer’S Disease, Shino D. Magaki

Loma Linda University Electronic Theses, Dissertations & Projects

Alzheimer’s disease (AD) is the most common form of senile dementia in the US and worldwide but the causes of its pathogenesis are currently unknown. In this study, we examined two processes that have been implicated in the early stages of AD and other forms of neurodegeneration, iron dysregulation and inflammation, both of which can promote the increased production of amyloid precursor protein (APP). We have measured different pools of brain iron in transgenic iron regulatory protein 2 knockout (IRP2-/-) mice in the early stages of neurodegeneration and in affected brain regions from AD patients at different stages of the …

The Effect Of Walnuts Compared To Fatty Fish On Plasma And Erythrocyte Fatty Acid Composition, Lymphocyte Subsets And Inflammatory Mediators, Yu-Lan Ching

Loma Linda University Electronic Theses, Dissertations & Projects

The purpose of this study was to compare the effects of walnuts vs. fatty fish on circulating inflammatory markers, on lymphocyte subsets, on plasma concentrations of eicosanoids precursor polyunsaturated fatty acid and on erythrocyte membrane fatty acid composition. Under controlled metabolic feeding conditions and randomized crossover (3x3 Latin-square) design, 27 subjects alternately consumed a control diet, a walnut diet (1.5 oz (42.5g) /day of walnuts, 6 times/week) or a fish diet (8 oz (226g) /week of salmon) for 4 weeks each. Consumption of the walnut diet (ALA 5.43 g/day) compared to the fish diet (EPA 170 mg/day and DHA 590 …