Molecular Biology Commons^™

Biological Clocks, Inflammation, And Multiorgan Damage In Sickle Cell Disease, Morayo Adebiyi

Dissertations and Theses (Open Access)

Sickle cell disease (SCD) is a dangerous condition caused by a genetic mutation on the human beta-globin gene that contributes to erythrocyte sickling, the hallmark of the disease. Previous metabolomics studies have confirmed that elevated sphingosine kinase 1 (SphK1) mediates sphingosine-1-phosphate (S1P) production to promote erythrocyte sickling. S1P signals via five S1P receptors (S1PR) regulates several pathophysiological functions.

In the first chapter of this dissertation, I explored the role of S1PRs in SCD by utilizing pharmacologic and genetic tools. To determine the role of S1P-S1PRs signaling in SCD, I treated humanized Berkeley sickle mice (Berkeley HBS mice), with FTY720, a …

The Interaction Between Ceramide-1-Phosphate And Group Iva Cytosolic Phospholipase A2 And Its Role In Wound Healing, Patrick Macknight

Theses and Dissertations

The sphingolipid, ceramide-1-phosphate (C1P), directly binds and activates Group IVA cytosolic phospholipase A₂ (cPLA₂a) to generate eicosanoids. Due to the role of eicosanoids in wound healing, we choose to use our novel genetic mouse model expressing cPLA₂a with an ablated C1P interaction site (KI) to examine the cPLA₂a/C1P interaction in wound healing. Wound closure rate was not affected, but wound maturation was dramatically enhanced by loss of the C1P/cPLA₂α interaction based on the following findings. Wounds in KI mice displayed: i) increased infiltration of dermal fibroblasts into the wound environment; ii …

Oxidative Stress And Inflammation In Hepatic Diseases: Current And Future Therapy., Karina Reyes-Gordillo, Ruchi Shah, Pablo Muriel

Biochemistry and Molecular Medicine Faculty Publications

Liver disease is a highly prevalent disease that is one of the leading causes of death worldwide. The continuous exposure of the liver to some factors such as viruses, alcohol, fat, and biotransformed metabolites can cause hepatic injury, which can lead to inflammation and liver degeneration. When the injury is sustained for long time, it can cause chronic liver diseases (CLDs), which include a spectrum of disease states ranging from simple steatosis and steatohepatitis (steatosis with inflammation and hepatocyte injury and death) to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Multiple evidences indicate that oxidative stress and inflammation are the most …

Clinicopathology And Molecular Determinants Underlying Benign Breast And Breast Cancer Lesions, Andreana Holowatyj Holowatyj

Wayne State University Dissertations

Despite converging incidence rates for breast cancers by race, disparities in mortality persist where black women suffer from poorer prognosis compared to white counterparts. To understand the clinical, demographic, and molecular characteristics underlying these disparities, we examined differences among patients with breast cancer to understand the role of human epidermal growth factor receptor 2 (HER2) status, age, and race/ethnicity among women diagnosed with hormone receptor-positive breast cancer, and disparities in surgical therapy among female patients with early stage young-onset breast cancer. Benign breast disease, another known risk factor for breast cancer, includes a histological spectrum of lesions, could contribute to …

Effect Of Endoplasmic Reticulum Stress On Vascular Smooth Muscle Cells And Its Regulation Of Sm22Α, Neeraja Priyanka Annam

Wayne State University Dissertations

Background: The vascular smooth muscle cells(VSMC) possess the ability to differentiate into a synthetic phenotype in response to stress. This phenotypic modulation may be accompanied by inflammatory or osteogenic response in chronic stress. The synthetic state is characterized by low levels of contractile markers unlike the differentiated state.

Hypothesis: Endoplasmic reticulum (ER) stress causes phenotypic modulation in VSMCs leading to apoptosis. Many transcription factors induced by ER stress contribute to the downregulation of Sm22α. Perturbation in cytoskeletal dynamics exacerbates the ER stress response.

Methods: Ex-vivo culture was used to establish importance of Sm22 in ER stress. In vitro analysis was …

Inflammatory Gene Expression In Women Diagnosed With Polycystic Ovarian Syndrome, Myles K. Taylor

Electronic Theses & Dissertations

Polycystic ovarian syndrome (PCOS) is a common endocrine disorder in women of reproductive age. The pathophysiology of PCOS has conventionally thought to originate from androgen excess. However, recent evidence suggests that androgen excess is a downstream consequence to inflammatory dysregulation and subsequent metabolic abnormalities. Inflammatory mRNA gene expression of TNFa and IL-1ß in mononuclear cells isolated from women diagnosed with PCOS was explored using qPCR. Additionally, the correlations between body mass index (BMI) and fasting glucose on mRNA expression of TNFa and IL-1ß were explored. mRNA expression of both TNFa and IL-1ß were found to be significantly higher in PCOS …

Extracellular Matrix Remodeling And The Inflammatory Response During Skeletal Muscle Regeneration In Sarcopenic Obese Mice, Lemuel Arthur Brown

Graduate Theses and Dissertations

AIM: Sarocpenic obesity is a national concern within the United States because this metabolic syndrome is tied with reduced mobility and quality of life. Both obesity and aging are associated with insulin-resistance, chronic low-grade inflammation and muscle weakness. Skeletal muscle regeneration is a process that involves the coordinated effort of myogenic regulatory factors (MRFs), inflammatory signaling, and extracellular matrix (ECM) remodeling for optimal regeneration. It has been demonstrated that obesity and aging have a reduction in muscle regeneration. It has not been examined if sarcopenic obesity will further reduce muscle mass and the regenerative process. The purpose of this study …

Palmitoyl Acyltransferase Dhhc21 Mediates Endothelial Dysfunction In Systemic Inflammatory Response Syndrome, Richard S. Beard Jr.

Biomedical Research Institute Publications and Presentations

Endothelial dysfunction is a hallmark of systemic inflammatory response underlying multiple organ failure. Here we report a novel function of DHHC-containing palmitoyl acyltransferases (PATs) in mediating endothelial inflammation. Pharmacological inhibition of PATs attenuates barrier leakage and leucocyte adhesion induced by endothelial junction hyperpermeability and ICAM-1 expression during inflammation. Among 11 DHHCs detected in vascular endothelium, DHHC21 is required for barrier response. Mice with DHHC21 function deficiency (Zdhhc21^dep/dep) exhibit marked resistance to injury, characterized by reduced plasma leakage, decreased leucocyte adhesion and ameliorated lung pathology, culminating in improved survival. Endothelial cells from Zdhhc21^dep/dep display blunted barrier dysfunction and …

Role Of Microrna-21 In Atherogenesis., Rihab Hamed-Berair

Electronic Theses and Dissertations

MicroRNA-21 (miR-21) is an evolutionarily conserved microRNA, abundant in most cardiovascular tissues. It has been implicated in the pathogenesis of several cardiovascular diseases including restenosis, myocardial infarction, and heart failure. However, little is known about the contribution of miR-21 in atherosclerosis. My data show that expression of miR-21 is increased by >1.5-fold in murine atherosclerotic lesions and by 1.5-2.0-fold in the macrophages of Western diet (WD)-fed LDLR-KO mice (for 12-20 weeks). In vitro, LDL, oxidized LDL, acetylated LDL and LPS induced miR-21 by 2-4-fold and down-regulated its target protein, PDCD4, in bone marrow-derived macrophages. Basally, macrophages isolated from miR-21-KO …

Preeclampsia: The Roles Of Acute Inflammation And Intrauterine Stress, Nicholas Parchim

Dissertations and Theses (Open Access)

Preeclampsia (PE) is a severe, acute disease of pregnancy affecting approximately 8% of pregnant women after week 20 of gestation. PE is characterized by hypertension and renal damage reflected by proteinuria and has significant morbidity to both mother and fetus. Maternal symptoms range from headaches, nausea, edema, to visual changes, but once maternal symptoms present, damage to the fetus has begun. Mothers who progress untreated through the disease can also experience a condition called eclampsia characterized by seizure, coma, and, ultimately, death. PE-affected newborns experience features similar to prematurity—abnormal lung and renal development, intrauterine growth retardation (IUGR), and, possibly, fetal …

Eliminating Acute Myeloid Leukemia Stem Cells By Targeting The Niche Microenviromnent: Co-Inhibition Of Tnf/Il1- Jnk And Nf-Κb, Andrew Volk

Dissertations

Leukemia Stem Cells (LSCs) from Acute Myeloid Leukemia (AML) require the activity of the transcription factor NF-kB to maintain stemness and drive tumor formation. Blocking NF-kB can preferentially eliminate LSCs in vitro with minimal effects on healthy Hematopoietic Stem and Progenitor Cells (HSPCs), making NF-kB a compelling target for anti-leukemia therapies. However, blocking NF-kB in vivo can only extend survival for a short period of time before transplanted mice succumb to the disease. I propose this is due to components of the in vivo niche supporting LSC survival and compensating for the inhibition of NF-kB.

I observed patients with partially …

Soy Isoflavones Mediate Radioprotection Of Normal Lung Tissue By Modulating The Radiation-Induced Inflammatory Response, Lisa Marie Abernathy

Wayne State University Dissertations

Radiation-induced lung injury (RILI) is caused by an early inflammatory process triggered by damage to lung parenchyma, epithelial cells, vascular endothelial cells and stroma. Initially, oxidative injuries after radiation induce altered expression of pro-inflammatory cytokines. Infiltrating inflammatory cells are stimulated and activated, producing additional mediators, resulting in a cytokine cascade. The expansion and perpetual activation of inflammatory cells, as well as lung parenchyma, lead to clinical pneumonitis. Activated cells produce molecular mediators and growth factors that affect the proliferation and gene expression of lung fibroblasts. This process leads to increased collagen synthesis and deposition, eventually leading to the development of …

The Interrelationship Of Brca1 185delag, Interleukin-1Β, And Ovarian Oncogenesis, Kamisha Woolery

USF Tampa Graduate Theses and Dissertations

While the etiology of ovarian cancer (OC) is not completely understood, evidence suggests that chronic inflammation may promote malignant transformation. However, familial history remains the strongest risk factor for developing OC and is associated with germline BRCA1 mutations, such as the 185delAG mutation. Normal human ovarian surface epithelial cells expressing the 185delAG mutant, BRAT, exhibit molecular and pathological changes that may contribute to OC oncogenesis. In the current study, I sought to determine whether BRAT could promote an inflammatory phenotype by investigating BRAT's impact on the expression of the proinflammatory cytokine, Interleukin-1β (IL-1β). Using a culture model system of normal …

Immature Myeloid Cells Promote Tumor Formation Via Non-Suppressive Mechanism, Myrna Lillian Ortiz

USF Tampa Graduate Theses and Dissertations

ABSTRACT

Although there is ample evidence linking chronic inflammation with cancer, the cellular mechanisms involved in early events leading to tumor development remain unclear. Myeloid cells are an intricate part of inflammation. They consist of mature cells represented by macrophages, dendritic cells and granulocytes and a population of Immature Myeloid Cells (IMC), which in healthy individuals are cells in transition to mature cells. There is a substantial expansion of IMC in cancer and many other pathological conditions which is associated with pathologic activation of these cells. As a result, these cells acquire the ability to suppress immune responses and are …

Mechanisms Of Age-Related Inflammation And Cancer : The Synergistic Effect Of Oxidants And Calcium, Donald A. Mccarthy

Legacy Theses & Dissertations (2009 - 2024)

The accumulation of senescent cells during the process of aging has been implicated as causal in numerous age-related pathologies. Senescent cells adopt a secretory phenotype consisting of many factors including matrix remodeling enzymes, growth factors, cytokines, and chemokines. Their secretory nature is the primary reason that they are associated with disease, but it remains unclear why they become so inflammatory. Using primary human fibroblasts cultured to senescence, we mechanistically determined why senescent cells are such potent inducers of inflammation. Our findings indicate that the early production of the cytokine Interleukin 1-α (IL-1α) is central to this transition. We found that …

A Defect In Interleukin 12-Induced Activation And Interferon Gamma Secretion Of Peripheral Natural Killer T Cells In Nonobese Diabetic Mice Suggests New Pathogenic Mechanisms For Insulin-Dependent Diabetes Mellitus., Marika Falcone, Brian Yeung, Lee Tucker, Enrique Rodriguez, Nora Sarvetnick

Journal Articles: Regenerative Medicine

The function of natural killer T (NKT) cells in the immune system has yet to be determined. There is some evidence that their defect is associated with autoimmunity, but it is still unclear how they play a role in regulating the pathogenesis of T cell-mediated autoimmune diseases. It was originally proposed that NKT cells could control autoimmunity by shifting the cytokine profile of autoimmune T cells toward a protective T helper 2 cell (Th2) type. However, it is now clear that the major function of NKT cells in the immune system is not related to their interleukin (IL)-4 secretion. In …

Production Of Interleukin 10 By Islet Cells Accelerates Immune-Mediated Destruction Of Beta Cells In Nonobese Diabetic Mice., Lise Wogensen, Myung-Shik Lee, Nora Sarvetnick

Journal Articles: Regenerative Medicine

The T helper type 2 (Th2) cell product interleukin 10 (IL-10) inhibits the proliferation and function of Th1 lymphocytes and macrophages (M phi). The nonobese diabetic mouse strain (NOD/Shi) develops a M phi and T cell-dependent autoimmune diabetes that closely resembles human insulin-dependent diabetes mellitus (IDDM). The objective of the present study was to explore the consequences of localized production of IL-10 on diabetes development in NOD/Shi mice. Surprisingly, local production of IL-10 accelerated the onset and increased the prevalence of diabetes, since diabetes developed at 5-10 wk of age in 92% of IL-10 positive I-A beta g7/g7, I-E- mice …