Medical Sciences Commons^™

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 …

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. …

Radiosensitization Of Head & Neck Carcinoma Cells By Linifanib, A Receptor Tyrosine Kinase Inhibitor, Heng-Wei Hsu

Loma Linda University Electronic Theses, Dissertations & Projects

Tumor angiogenesis is a hallmark of advanced cancers and promotes invasion and metastasis. Over 90% of head and neck squamous cell carcinomas (HNSCC) express angiogenic factors such as vascular endothelial growth factor (VEGF). Since radiotherapy is one of the most commonly used treatments for HNSCC, it is imperative to identify the interactions between antiangiogenic therapy and radiotherapy, and to develop combination therapy to improve clinical outcome. The mechanisms between antiangiogenic agents and ionizing radiation are complicated and involve many interactions between the vasculature, tumor stroma and tumor cells. The proliferation and metastasis of tumor cells rely on angiogenesis/blood vessel formation. …

Role Of Vimf In Gingipain Maturation In Porphyromonas Gingivalis, Arun S. Muthiah

Loma Linda University Electronic Theses, Dissertations & Projects

Gingipain activity in Porphyromonas gingivalis, the major etiological agent in adult periodontitis, is post-translationally regulated by unique Vim proteins including VimF, a putative glycosyltransferase. To ascertain the VimF mediated phenotype we first inactivated the vimF gene in P. gingivalis ATCC 33277 (FLL476), a less virulent fimbriated strain. We observed that the vimF-defective mutant (FLL476) showed a phenotype similar to that of the vimF-defective mutant (FLL95) in the P. gingivalis W83 background. While hemagglutination was not detected and autoaggregationn was reduced, biofilm formation was increased in FLL476. Also, invasive capacity decreased for this mutant. Furthermore, fimbrial structures were missing in FLL476, …

Vegf And Sympathetic Perivascular Nerves Contribute To Hypoxic Remodeling Of Ovine Cranial Arteries, Olayemi Olufikayo Adeoye

Loma Linda University Electronic Theses, Dissertations & Projects

Chronic hypoxia complicates many pregnancies and can result in postnatal pathologies that include compromised fetal cardiovascular structure and function. Mechanisms involved remain unclear. Because hypoxia increases production of VEGF, known to modulate smooth muscle (SM) phenotype, this thesis explored the hypothesis that VEGF contributes to hypoxic fetal vascular remodeling through direct effects on SM cells and indirectly through perivascular nerves. Using a chronic hypoxia sheep model, this work demonstrated that: 1) hypoxia potently upregulates VEGF receptor expression but not endogenous VEGF level in fetal ovine carotid arteries; 2) both chronic hypoxia and VEGF exert similar effects on smooth muscle contractile …

Effect Of Procedural Pain On Purines, Mda And Allantoin In Premature Infants, Megan Sue Holden

Loma Linda University Electronic Theses, Dissertations & Projects

Identifying and measuring the biochemical effects of procedural pain in infants is a continuing challenge for clinicians. To address this issue we evaluated the relationship between procedural pain, ATP utilization (hypoxanthine and uric acid), and oxidative stress (MDA and allantoin) in premature infants. Through these studies we found that 1) a single heel-lance significantly increases plasma uric acid in rabbit kits, 2) tape removal increases MDA and prevents a decrease in uric acid in the plasma of premature infants, and 3) a single dose of oral sucrose before a heel-lance is sufficient to significantly increase plasma markers of ATP utilization …

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 …

Role Of Igf-Ii, Prl, And Fabps In The Breast Cancer Disparity Among Aa Women, Teleka Cassandra Patrick

Loma Linda University Electronic Theses, Dissertations & Projects

It is well documented that African-American (AA) patients present with more advanced states of breast cancer and have lower survival rates than Caucasian-Americans (CA). Epidemiological data have shown that pregnancy and lactation at an early age in humans reduce the risk of breast cancer. Studies in mice and rats have shown that lactation stimulates the expression of intracellular fatty-acid binding protein 3 (FABP3). FABP3 is detected in human breast tissue and is known as mammary-derived growth inhibitor (MDGI) because it has a strong inhibitory effect on cell proliferation. FABP5 is also expressed in the breast, and has been associated with …

Microglia And Complement In Alzheimer's Disease With Cerebral Amyloid Angiopathy, Matthew K. Zabel

Loma Linda University Electronic Theses, Dissertations & Projects

Alzheimer’s disease (AD) is the most common form of dementia and completely lacks any viable, long-term therapeutic intervention. This is partly due to an incomplete understanding of AD etiology and the possible confounding factors associated with its genotypic and phenotypic heterogeneity. Cerebral amyloid angiopathy (CAA) is a common, yet frequently overlooked, pathology associated with AD. A pathological hallmark of AD consists of extracellular amyloid-beta (Aβ) deposits, while CAA

manifests with deposition Aβ within the smooth muscle layer of cerebral arteries and arterioles. The role of Aβ in AD and CAA pathophysiology has long been controversial. Although it may have toxic …

Perinatal Nicotine Exposure And Programming Of Hie Sensitive Phenotype In Neonatal Rat Brains, Yong Li

Loma Linda University Electronic Theses, Dissertations & Projects

Large epidemiological and animal studies have revealed a clear association of adverse intrauterine environment with the increased risk of metabolic, cardiovascular and neurological diseases. Maternal smoking is the single most widespread perinatal insult in the world and has been associated with adverse pregnancy outcomes for mother, fetus and the newborn. Our study aims to test the hypothesis that perinatal nicotine exposure induces reprogramming of susceptibility to hypoxic ischemic brain injury in the immature brain, focusing on the roles of AT1R and/or AT2R and trying to reveal the underlying epigenetic mechanisms. Therefore, we established two rat models: perinatal nicotine exposure model …

Regulation Of Igfbp-5 And Osteoblast Functions By Nuclear Factor I, Laura A. Perez-Casellas

Loma Linda University Electronic Theses, Dissertations & Projects

The Insulin-like Growth Factor (IGF) system is a major target of GC inhibition in bone. We found that GCs inhibit expression of IGF binding protein-5 (IGFBP5) which binds IGFs and stimulates osteoblast activity by IGF dependent and independent mechanisms. GC-induced inhibition of IGFPB5 promoter activity was mediated by a composite response element that has binding sites for transcription factor activator protein 2 (AP-2) and nuclear factor I (NFI). The work in this dissertation identifies the NFI gene family as an important regulator of IGFBP-5 transcription primarily in human, as well as murine osteoblasts. The mechanism of IGFBP5 gene regulation involves …

Role Of The Pituitary-Adrenal Axis In G-Csf Therapy After Neonatal Hypoxia-Ischemia, Melissa Stephanie Charles

Loma Linda University Electronic Theses, Dissertations & Projects

Several reports indicate that the activity of the hypothalamic-pituitary-adrenal axis (HPA) as measured by the increased level of adrenocorticotropic hormone (ACTH), and corticosterone is increased after a brain insult. These hormones are the effectors secreted respectively by the pituitary and adrenal glands. It has been shown that the down-regulation of corticosterone levels can improve detrimental outcomes associated with ischemic brain injuries. Neonatal hypoxia-ischemia (HI) is a devastating perinatal event with a grim prognosis and limited therapeutic strategies. In recent studies, granulocyte-colony stimulating factor (G-CSF) has shown promise in neonatal HI investigations by improving neuromotor function and reducing apoptosis in the …

Mechanism Of Lmx1b-Regulated Limb Dorsalization, Jennifer Feenstra

Loma Linda University Electronic Theses, Dissertations & Projects

Lmx1b, a LIM homeodomain transcription factor is necessary for limb, kidney, eye, and central nervous system development. Lmx1b knockout (KO) mice display; abnormal limb dorsalization with distal ventral-ventral limbs, nephropathy, ocular malformations, loss of dopaminergic/serotonergic neurons, and reduced cerebellum and tectum formation. The developmental mechanisms utilized by Lmx1b remain largely unknown; to investigate downstream targets, we have used the limb as a model because of its accessibility and striking Lmx1b KO phenotype. To identify candidate genes, we compared gene arrays from Lmx1b KO and wildtype mouse limbs during limb dorsalization, i.e., 11.5, 12.5, and 13.5 days post coitum. We identified …

Analysis Of Minocycline As A Radioprotectant, Shalini Mehrotra

Loma Linda University Electronic Theses, Dissertations & Projects

Exposure to radiation is increasing in a variety of settings including space exploration, diagnostic medical procedures and radiotherapy. Cells of the hematopoietic system, such as white blood cells (WBC), are especially sensitive to radiation and their decline can result in Acute Radiation Syndrome (ARS). Radiotherapy is often used for cancers of the central nervous system (CNS), but includes the risk for normal tissue damage, often leading to cognitive impairment. The literature suggests that tetracyclines can be radioprotectors of the hematopoietic system with potential utility in radiation emergencies and anticancer radiotherapy. Minocycline, a semisynthetic tetracycline derivative, has anti-inflammatory, free radical scavenging, …

Kinetically Controlled Synthesis Of Triblock Copolymer Stabilized Gold Nanoparticles, Theodore Saleem Sabir

Loma Linda University Electronic Theses, Dissertations & Projects

Concerns for the environmental and economic impact of organic solvents in gold nanoparticle synthesis have motivated the search for more environmentally benign alternatives. One viable approach is the synthesis of AuNPs from tetrachloroauric(III) acid (HAuCl4) using triblock copolymers (TBPs). However, a major challenge of using TBPs is the heterogeneous nature of the formed nanocrystals. Establishing control over AuNP size and shape requires a detailed mechanistic understanding of precursor reduction and nanoparticle growth. By using mixtures of TBPs (L31 and F68), a more flexible method to tune AuNP size and shape is demonstrated. This is achieved by adjusting the TBP/Au(III) ratio …

Effect Of Maternal Hypoxia On The Cerebral And Cardiac Tissue Remodeling, Wenni Tong

Loma Linda University Electronic Theses, Dissertations & Projects

Large epidemiological studies and animal studies have indicated a clear association of adverse intrauterine environment with an increased incidence of low birth weight, perinatal mortality, and cardiovascular disease in later adult life. In humans, one of the most common stresses in utero is hypoxia. The goal of this project is to test the hypothesis that fetal hypoxia causes reprogramming of MMPs and TIMPs expression patterns and activities leading to aberrant brain and heart development in the fetuses and neonates. In the first part of project, we tested the hypothesis that maternal hypoxia increases the activity of MMPs and decreases the …

The Impact Of Nucleoside Sugar Modification On Biochemical Dna Transactions, Adides Williams

Loma Linda University Electronic Theses, Dissertations & Projects

Discrimination by DNA polymerases controls the fidelity of DNA replication, and reduced fidelity results in mutations essential in the etiology of cancer. Polymerase discrimination operates at both dNTP insertion and subsequent elongation steps, and involves several energetic and structural factors that are as yet incompletely understood. While base pairing interactions have been studied extensively, substantially less is known about the role of sugar structure and conformation for polymerase incorporation and extension. In these studies we examined, systematically, the role of sugar structure and conformation on polymerase selection of the dNTP for insertion and polymerase elongation. To accomplish these goals, we …

Mechanisms Of Brain Edema Formation In Mouse Models Of Intracerebral Hemorrhage, Qingyi Ma

Loma Linda University Electronic Theses, Dissertations & Projects

Perihematomal edema causes major neurologic deterioration following intracerebral hemorrhage (ICH), mainly resulting from the disruption of the blood-brain barrier (BBB) by multiple mediators, including inflammatory mediators and thrombin. The objective of our study was to investigate the mechanisms by which inflammation and thrombin respectively lead to the formation of brain edema following ICH. Our long-term goal is to develop new therapeutic strategies against ICH-induced brain edema by targeting: (1) VAP-1 mediated inflammatory response and (2) PDGFR-α orchestrated BBB impairment. Vascular adhesion protein-1 (VAP-1) was previously shown to promote leukocyte adhesion and transmigration. Additionally, PDGFR-α was also found to play a …

Role Of Vima In Cell Surface Biogenesis In Porphyromonas Gingivalis, Devon Osbourne Jr.

Loma Linda University Electronic Theses, Dissertations & Projects

Porphyromonas gingivalis is an important etiological agent of periodontal disease - a disease that affects an estimated 49,000,000 people in the United States of America. Periodontal disease includes gingivitis – inflammation of the gums, and periodontitis – destruction of the teeth and their supporting tissues. Porphyromonas gingivalis is associated with the chronic form of periodontal disease in addition to several systemic diseases.

The vimA gene of P. gingivalis has been previously shown to play a significant role in the biogenesis of gingipains (trypsin-like cysteine proteases). The vimA has also been demonstrated to play a role in hemolysis, hemagglutination, autoaggregation, posttranslational …

Chronic Hypoxia Induces Epigenetic Modifications In The Fetal Rat Heart, Andrew James Grant Patterson

Loma Linda University Electronic Theses, Dissertations & Projects

Heart disease remains the leading cause of death worldwide. As a result of studies done by Barker and associates, our awareness of the significance of stress during gestation as a risk factor for heart diseases has expanded. We now know that events in utero can significantly alter gene expression patterns in heart tissue leading to increase susceptibility to ischemia reperfusion injury in adulthood. The focus of this project was to elucidate the role of chronic hypoxia in the programming of the cardio-protective gene, Protein Kinase C epsilon (PKCε) in fetal rat heart. We used an animal, organ base, and cell …

Mechanisms Of Erythropoietin-Induced Neuroprotection In: In-Vivo And In-Vitro Models Of Hypoxia Ischema, Rhonda Andrea Souvenir

Loma Linda University Electronic Theses, Dissertations & Projects

Hypoxic ischemic brain injury (HIBI) is a common cause of neonatal mortality and morbidity. Approximately 60 % of preterm babies and 2% of full term infants suffer from asphyxia. Asphyxia related death accounts for approximately 23% of neonatal mortality annually. Many therapeutic interventions show promise in the laboratory but fail in clinics. A thorough understanding of mechanisms by which promising therapeutic intervention confers its neuroprotection is necessary to promote smoother transitions from bench to the bedside. Erythropoietin (EPO), a hematopoietic growth factor that increases oxygen availability during hypoxia/ischemia is associated with cell survival and neuroprotection in: in vivo and in …

Characterization Of Palmitic Acid Induced Lipotoxicity In Schwann Cells, Amelia Padilla

Loma Linda University Electronic Theses, Dissertations & Projects

Lipotoxicity is a response to lipid overload that has been associated with cellular dysfunction leading to cellular death. The mechanism of lipotoxicity and its impact on the nervous system is critical as it can lead to debilitating neurological conditions. This study examines key cellular events induced by palmitic acid lipotoxicity (PA-LTx) in Schwann cells cultured in euglycemic and hyperglycemic conditions. The data show that immortalized Schwann cell (iSC), as well as primary Schwann cell (pSC) cultures exposed to elevated levels of PA induced an apoptotic cell death that is dose and time-dependent. The earliest indication of cellular dysfunction was a …

Biochemical And Functional Characterization Of The Ledgf/P75-Mecp2 Interaction In Tumor Cells, Lai Sum Leoh

Loma Linda University Electronic Theses, Dissertations & Projects

The lens epithelial derived growth factor p75 (LEDGF/p75) is a novel pro-survival and stress-inducible transcription co-activator that protects mammalian cells from various environmental stresses such as oxidative stress, heat shock, and serum starvation. This emerging cancer-related protein is highly expressed in prostate tumors and other tumor types and promotes resistance to chemotherapy in cancer cells. LEDGF/p75 is also involved in acquired immunodeficiency syndrome (AIDS) since it interacts with HIV-1 integrase to facilitate the integration and replication of the HIV virus in human cells. In addition, LEDGF/p75 has been shown to interact with MLL (mixed lineage leukemia)/menin transcription complex in leukemia …

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 …

Lateralization Of Emotion, Reaction Time, And Skin Conductance Responsiveness, Kimberley Erin Rose

Loma Linda University Electronic Theses, Dissertations & Projects

Bilateral presentations of brief (250 ms), unmasked emotional and neutral stimuli were examined in two experiments with primarily female samples. Reaction time and accuracy data were used to measure perception of emotion and skin conductance response (SCR) was used to measure experience of emotion. Both words and pictures were used to account for hemispheric differences in language and visuospatial dominance. Response time was faster to emotional pictures than words. Reaction time and speeded accuracy data did not support right hemisphere hypothesis (RHH) or valence hypothesis (VH) in the expected manner. Data suggested emotion caused greater interference under speeded conditions in …

Dynamic Contrast-Enhanced Mri Of Pancreatic Islet Transplants, Nathaniel K. Chan

Loma Linda University Electronic Theses, Dissertations & Projects

Since its discovery in 1922, insulin has been the life-saving treatment for type 1 diabetes mellitus. As the disease is caused by the loss of insulin-producing pancreatic islets, transplantation of donor islets has the potential to not only supplement insulin replacement therapy but to cure type 1 diabetes. However, long-term insulin independence (> 2 years post-transplant) remains a challenge partly due to low islet blood flow immediately following transplantation leading to hypoxic stress on islets. The goal of our studies is to improve islet engraftment by monitoring and promoting the regrowth and maturation of new islet blood vessels in a …

Dna Repair Of 8-Oxo-7,8-Dihydroguanine Lesions In Porphyromonas Gingivalis, Leroy G. Henry Jr.

Loma Linda University Electronic Theses, Dissertations & Projects

The persistence of Porphyromonas gingivalis in the inflammatory environment of the periodontal pocket requires an ability to overcome oxidative stress. DNA damage is a major consequence of oxidative stress. Unlike other organisms, a non-base excision repair mechanism for the removal of 8-oxo-7,8-dihydroguanine (8-oxoG) in P. gingivalis was suggested. Because the uvrB gene is known to be important in nucleotide excision repair, the role of this gene in the repair of oxidative stress-induced DNA damage was investigated. A 3.1 kb fragment containing the uvrB gene was PCR-amplified from the chromosomal DNA of P. gingivalis W83. This gene was insertionally inactivated using …

Novel Molecules That Regulate Bone Formation And Bone Resorption, Gabriel Robert Linares

Loma Linda University Electronic Theses, Dissertations & Projects

Osteoporosis is a disease characterized by decreased bone mass and microarchitectural deterioration of bone. Bone loss occurs when the increased bone resorption that occurs with age is not compensated by a corresponding increase in bone formation. Therefore, understanding the mechanisms which regulate bone formation and bone resorption is important for developing diagnostic and treatment strategies for osteoporosis. In my dissertation, we investigated the role of Glutaredoxin 5 (Grx5), Diabetes and Obesity Related protein (DOR), and Claudin 18 (Cldn-18), novel molecules involved in regulating bone formation and bone resorption. We demonstrated that Grx5 protects osteoblasts from oxidative stress induced apoptosis via …

Nanomaterials And Block Copolymers For Overcoming Multidrug Resistance In Cancer, Wesley Livingstone

Loma Linda University Electronic Theses, Dissertations & Projects

The development of multidrug resistance in cancer is one of the leading causes for decreased chemotherapy efficacy and is particularly threatening to aggressive cancers such as that of the pancreas. In cancers where chemotherapy is amongst the few treatment options, it is crucial to develop chemotherapeutics that either bypass or control the development of multidrug resistance. Polymeric nanomaterials such as Pluronics® are of current interest due to their ability to perform these functions in addition to enhancing pro-apoptotic mechanisms. Using the respectively known chemosensitive and chemoresistant pancreatic adenocarcinoma cell lines MiaPaCa-2 and PANC-1, an in vitro analysis of the synergistic …

Influence Of Gender And Aerobic Training Background On Exercise-Induced Increase In Adiponectin, Pooja Pratap Mujumdar

Loma Linda University Electronic Theses, Dissertations & Projects

Adipose tissue secretes the adipokine, adiponectin (ADPN), which is insulinsensitizing, anti-inflammatory, and anti-atherogenic. Exercise training improves insulin sensitivity and lowers the risk of cardiovascular complications. As some of the metabolic effects of exercise training and ADPN overlap, exercise training has been proposed to increase ADPN. However, most single bout exercise, or short-term (ï‚£3 months) and constant-effort (fixed session duration, fixed number of sessions/week, and fixed intensity) exercise protocols do not produce increases in ADPN in untrained and trained cohorts. Furthermore, most exercise studies were conducted on male-female mixed gender cohorts or male/female single gender cohorts. As a result, no direct …