Medical Molecular Biology Commons^™

Kras-Independent Factors Drive Pi3k Signaling And Circumvent The Necessity Of Kras-Driven Pi3k Activation In Pdac, Lucas Christopher Bialousow

MUSC Theses and Dissertations

Pancreatic ductal adenocarcinoma (PDAC) has one of the lowest five-year survival rates among cancers and is characterized by near-ubiquitous occurrence of oncogenic KRAS mutations. Oncogenic KRAS activates several downstream pathways, including ERK 1/2 MAPK and PI3K, which are critical for PDAC. However, accumulating evidence suggests that PI3K activity can be maintained independent of oncogenic KRAS. The high prevalence of KRAS^G12R in PDAC challenges the prevailing model of KRAS-driven PI3K activation, as this mutant is defective in direct engagement with PI3Kα. These observations raise important questions regarding how PI3K signaling is sustained in PDAC. Here, we investigated KRAS-independent mechanisms that …

A Long Non-Coding Erna Forms R-Loops To Shape Emotional Experience-Induced Behavioral Adaptations, Rose Marie Akiki

MUSC Theses and Dissertations

Emotional experiences often evoke neural plasticity that supports adaptive changes in behavior, including maladaptive plasticity associated with mood and substance use disorders. These adaptations are supported in part by experience-dependent activation of immediate-early response genes, such as Npas4. We discovered that a conserved, long non-coding enhancer RNA (lnc-eRNA) transcribed from an activity-sensitive enhancer produces DNA-RNA hybrid R-loop structures that support 3D chromatin-looping of the enhancer and proximal promoter and stimulus-induced, rapid Npas4 gene induction. We also show that this Npas4 lnceRNA and its R-loops are required for the development of behavioral adaptations produced by chronic psychosocial stress or cocaine exposure, …

Myod Functions As An Oncogene In Rhabdomyosarcoma By Promoting Survival Through Differentiation And Cyld, Alexander Oles

MUSC Theses and Dissertations

Rhabdomyosarcoma (RMS) is the most common soft tissue cancer among

children, characterized by a skeletal muscle lineage that is impaired from

undergoing terminal differentiation. NF-κB is constitutively active in cancer cells

and plays a critical role in cell survival. Although NF-κB is also activated in RMS,

surprisingly we find that these tumors are less dependent on NF-κB to overcome

stress-induced cell death. Instead, RMS cells survive by being partially

differentiated under the control of the myogenic transcription factor MyoD. Loss of

MyoD or cellular reprogramming dedifferentiates RMS tumor cells and promotes

cell death when exposed to stress. Further, use of …

Novel Mechanisms Of Systemic Sclerosis-Associated Lung Fibrosis, Joe E. Mouawad

MUSC Theses and Dissertations

Systemic sclerosis (SSc), also known as scleroderma, is an autoimmune disorder that affects the connective tissues and has the highest mortality rate among the rheumatic diseases. One of the hallmarks of SSc is fibrosis, which may develop systemically, affecting the skin and virtually any visceral organ in the body. Fibrosis of the lungs leads to interstitial lung disease (ILD), which is currently the leading cause of death in SSc. The identification of effective treatments to stop or reverse lung fibrosis has been the main challenge in reducing SSc mortality and improving patient outcomes and quality of life. Currently, only two …

A Retrospective Analysis On Quality Safety Outcomes In Patients Who Boarded In The Emergency Department With Syncope Or Near Syncope: Comparison Of Patient Bed Location And Admitting Service Area, Tamala S. Bradham

MUSC Theses and Dissertations

Patients presenting with the primary complaint of syncope or near syncope (PSNS) in the emergency department (ED) represents 11.9 million annual visits nationally with an estimated annual cost of over $2.4 billion. With an increase in ED patient visits and limited inpatient bed availability, patients are "boarding" in the ED for extended periods of time. Our aim was to assess whether first available bed assignment, regardless of the admitting service area, would negatively affect major quality patient safety indicators for PSNS. We completed a retrospective cohort study of 659 patients who visited a US southeast academic medical center over a …

Activation Of Protein Phosphatase 2c By Ceramide And Essential Role Of Acid Sphingomyelinase In Interleukin-6 Synthesis, David Mark Perry

MUSC Theses and Dissertations

Since their discovery over a century ago, sphingolipids have riddled and fascinated the scientific community with benchmarks of progress including the identification of the enzymatic defects in the lysosomal storage diseases and the discovery of their involvement in cellular processes. Excluding sphingosine-1-phosphate with its associated G-protein coupled receptors, a staggering gap still persists in our understanding of the mechanisms related to the functions of the sphingolipids, ceramide and sphingosine. Moreover, in spite of the impressive amount of literature implicating ceramide in biological processes, precise and well-documented roles in biology for specific ceramide-producing enzymes are surprisingly rare. To further investigate the …

The Epigenetic Regulation Of Cubilin And The Physiological Role Of This Receptor In Maintaining The Homeostasis Of Serum Albumin And Hdl, Sayed Obaidullah Aseem

MUSC Theses and Dissertations

Cubilin is an endocytic receptor capable of mediating the endocytosis of multiple ligands including High Density Lipoprotein apolipoprotein A-I (apoA-1) and albumin. It is highly expressed on the epithelium of intestinal villi and renal proximal tubules. In the kidney, endocytosis mediated by cubilin and its co-receptor megalin is the principal mechanism for proximal tubule reabsorption of filtered proteins, such as albumin and apoA-1. Yet, the consequences of cubilin deficiency on the blood levels of albumin and apoA-1 have not been studied. Furthermore, cubilin is downregulated in chronic diseases such as diabetes. However, little is known about the regulation of cubilin …

Role Of Protein Kinase Phosphorylation On Sert Oligomerization: A Novel Mechanistic View, Eric Richard Buck

MUSC Theses and Dissertations

The serotonin transporter (SERT) is the primary mechanism for the termination of synaptic signaling. It is of clinical relevance because it is a high-affinity target for therapeutics such as anti-depressants (SSRIs) and drugs of abuse such as cocaine, amphetamine, and 3,4 methylenedioxymethamphetamine (ecstasy). It is also seen as a protein potentially involved in the etiology underlying disorders such as clinical depression, autism, anxiety-related disorders, obsessive compulsive disorder, and anorexia nervosa among others. SERT has also been found to be a target of protein kinases that exert their effects through phosphorylation. For example, activation of protein kinase C (PKC) decreases SERT …

The Pericentrion: Identification, Characterization, And Function Of A Novel Cpkc-Dependent Compartment, Kevin P. Becker

MUSC Theses and Dissertations

Members of the protein kinase C (PKC) superfamily transduce a myriad of transmembrane signals initiated by the formation of sn-l ,2-diacylglycerol (DAG). As the primary physiological agonist for C] domain containing PKC isoenzymes, DAG functions to regulate the spatial and temporal parameters of PKC activity. It is now recognized that cellular DAG levels can vary from minutes to hours and even days. These observations have suggested a division of PKC functions that correlate to the duration of the cellular DAG signal. In their classical role, cPKCs respond acutely to the short-lived (1-2 min) DAG generated at the plasma membrane by …

Regulation Of The Ncx1 Gene In The Normal And Hypertrophied Myocardium, Kimberly Victoria Barnes

MUSC Theses and Dissertations

The sodium-calcium exchanger (NCX1) plays a major role in calcium efflux, and therefore, in calcium homeostasis in the heart. The exchanger mRNA and protein is rapidly upregulated within one hour of pressure overload. In this work, the exchanger has been shown to be upregulated by persistent pressure overload for at least one to two weeks. The 5' end of the NCX1 gene has been characterized in order to examine transcriptional regulation of the cardiac promoter. Four feline NCX1 isoforms of the 5' untranslated region have been cloned: one from brain (Br1), one from kidney (K1), and two from heart (H1 …

The Relationship Between Socioeconomic Factors, Attitudes, And The Frequency Of Pap Smears Of Female Patients In A Rural Health Care Center, Kathy Ann Barnes

MUSC Theses and Dissertations

Fifty-seven women over the age of 16, seeking care at a rural health center, completed questionnaires concerning demographic factors and health beliefs and attitudes. Correlation coefficients and Z scores were computed for the variables. There was significant positive correlation in both demographic and health belief and attitude areas. Discussed also are factors possibly contributing to the test results, as well as alternative research models.