Medical Sciences Commons^™

The Role Of Collagen Interacting Proteins In The Pathogenesis Of Filifactor Alocis, Ozioma Salomey Chioma

Loma Linda University Electronic Theses, Dissertations & Projects

Filifactor alocis is a Gram-positive, asaccharolytic; obligate anaerobe that has emerged as a potential periodontal pathogen due to its presence in high numbers in patients who have periodontal disease and least detection in healthy individuals (Kumar et al., 2003, Kumar et al., 2006, Wade, 2011). There is compelling evidence in the literature that demonstrates that F. alocis has virulence properties that may play an important role in infection-induced periodontitis (Abusleme et al., 2013, Griffen et al., 2012, Hutter et al., 2003, Khader et al., 2006, Siqueira and Rocas, 2003, Siqueira et al., 2009). However, there is a gap in our …

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 …

Molecular Mechanisms That Govern Human Cardiac Stem Cell Age Disparity, Tania Fuentes

Loma Linda University Electronic Theses, Dissertations & Projects

Transplantation of adult endogenous cardiovascular progenitor cells for heart repair results in some clinical benefit, however these stem cells lack the regenerative capacity unique to neonatal cardiovascular stem cells. The goal of this work was to identify mechanisms that contribute to the decline of cardiac stem cell regenerative ability with age and investigate novel therapeutic strategies to improve cardiac stem cell function. When comparing neonatal and adult cardiovascular stem cell clones, both cell types were capable of cardiomyogenic differentiation. However, the expression levels of forty-one microRNAs were significantly altered with age. Expression differences were correlated with reduced proliferation and a …

Towards A Better Treatment Of Parkinson's Disease, Bradley Darryl Karain

Loma Linda University Electronic Theses, Dissertations & Projects

Current therapies for Parkinson's Disease, the second most common neurodegenerative disorder, do not prevent disease progression, and induce extremely detrimental side-effects. Improving the best current pharmacological therapy, L-DOPA, carries important clinical benefits, partly by reducing the dose-related side-effects which occur after five to ten years of use. Thus the central aim of this proposal is to determine whether low doses of a D2 antagonist may, by selectively blocking the dopamine autoreceptor-mediated feedback inhibition of dopamine neurons, potentiate L-DOPA's effect on individual basal ganglia neurons and its antiparkinsonian effects in Parkinsonian animals. Electrophysiology (extracellular single-cell recording in the globus pallidus) and …

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 …

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, …

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 …

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 …

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 …

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 …

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 …

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 …

Igf2 Promotes Activation Of Estrogen Receptors In Basal-Like Breast Cancer Cells, Angelique Richardson

Loma Linda University Electronic Theses, Dissertations & Projects

The autocrine-paracrine effects of IGF2 are important in the growth and differentiation of normal breast. In breast cancer (BC), IGF2 is initially stimulated by estrogen, progesterone and prolactin to regulate proliferation and cancer progression. These actions are mediated by the IGF-1R and insulin receptor A (IR-A) both members of the tyrosine- kinase receptors family. The activation of Estrogen Receptor (ER) is also very important in BC growth and progression. As BC progresses to estrogen-independent growth, the IGF-1R and the estrogen receptor (ER) interact in crosstalk mechanisms that are synergistic and results in enhanced activation of both receptors signaling cascades. This …

P14arf : A P53-Independent Tumor Suppressor, Monte W. Miller

Loma Linda University Electronic Theses, Dissertations & Projects

Many genetic alterations at the CDKN2A locus on human chromosome 9 have been shown to be at least partially responsible for transformation of cells to a cancerous phenotype. This locus encodes two proteins, p16 and p14, that play a pivotal role in tumor surveillance.

Breakdowns in the p14 pathway have been estimated to be present in approximately 40% of human cancers and only recently have its binding partners and effects begun to be defined. Its interaction with the p53 pathway, which is estimated to be inactivated or mutated in 50% of all cancers, makes it difficult to determine its own …

Chronic Hypoxia, Exercise Training, And Skeletal Muscle Capillarity: Angiogenic Regulation And Morphological Consequences, Ivan Mark Olfert

Loma Linda University Electronic Theses, Dissertations & Projects

Angiogenesis is important in health and disease. In particular, exercise training is known to increase skeletal muscle capillarity, providing there is sufficient training intensity. The stimulus for this may be intracellular hypoxia activating angiogenic growth factor gene expression. Acute hypoxia alone has been shown to increase the gene expression of several key angiogenic regulators, e.g. vascular endothelial growth factor (VEGF) and to a lesser degree transforming growth factor-β1 (TGF-β1), basic fibroblast growth factor (bFGF), and thrombospondin-1 (TSP-1), an endogenous negative angiogenic regulator. Paradoxically, however, chronic hypoxia is generally not found to increase mammalian skeletal muscle capillarity. Accordingly, we hypothesized that …

Maternal Immunomodulation Of Neonatal Alloantigen Response, Leh Chang

Loma Linda University Electronic Theses, Dissertations & Projects

Remarkable success has been achieved in the transplantation of allogeneic cardiac grafts into newborn infants at Loma Linda University Medical Center. The superior graft survival rate documented in these patients has not correlated with the degree of immunosuppression rendered, or the selection of genetically matched donors. However, the clinical success has correlated with the age of the recipient at the time of receiving a transplant. Patients receiving an allograft within the first few weeks of life are unique in that they seem to accept the alloantigens of their cardiac graft while responding aggressively to antigens in their environment. These observations …