Cell and Developmental Biology Commons^™

Sufu In Shh Signalling Mediated Myogenesis, Suleyman Abdullah

Electronic Thesis and Dissertation Repository

Myogenesis is defined as the formation of skeletal muscle tissue during embryonic development and involves a multitude of cellular signalling pathways. Among these include the Sonic hedgehog (Shh) signalling pathway which must be deactivated for differentiation into muscle cells to occur. However, less is known regarding the pathways operation during cell differentiation and whether Suppressor of Fused (SUFU), the protein inhibitor of Shh signalling, plays a role. To address this, mouse C2C12 myoblast cells were utilized as a model and differentiated into muscle cells to identify the presence of SUFU during this time. Experiments in qRT-PCR show a decrease in …

Pathogenicity Of Acinetobacter Calcoaceticus, Kaitlan A. Sullivan

MUSC Theses and Dissertations

Acinetobacter is a genus of gram-negative bacteria that have been appearing frequently in hospitals contributing to infections in the blood, lungs, urinary tract, and other parts of the body. It infects patients with weakened immune systems that are placed on ventilators, after the use of catheters, or have any other open wounds produced by prolonged hospital stays. This genus of bacteria is problematic due to its high probability of becoming resistant to multiple classes of antibiotics. Thus, we are determining the pathogenicity of clinical isolates of Acinetobacter calcoaceticus using the organism Caenorhabditis elegans as a model.

We are testing …

Characterization Of Human Fibroblast Growth Factor 2 Variant To Determine Effects On Structure, Stability, And Cell Proliferation, Ryan Layes

Graduate Theses and Dissertations

Fibroblast growth factors (FGFs) are a family of cell signaling proteins conserved across multiple species. Each individual FGF elicits different cellular functions including, but not limited to, proliferation, migration, differentiation, angiogenesis, and wound healing. One of the most studied members, fibroblast growth factor 2 (FGF2), has demonstrated substantial wound healing capacity in a wide range of tissues including skeletal, muscular, neural, respiratory, epithelial, and cardiovascular. This ability makes FGF2 a potential therapeutic for a wide range of conditions and injuries. However, due to a short half-life at room temperature, therapeutic use of FGF2 is limited. It has been demonstrated that …

Characterization Of The Effects Of The Pyrazolopyrimidine Inhibitor Grassofermata (Nav-2729) In The Eukaryotic Pathogen Trypanosoma Brucei, Kristina Marie Parman

All Dissertations

The protozoan pathogen, Trypanosoma brucei, is the causative agent of sleeping sickness in humans and nagana in livestock in sub-Saharan Africa. T. brucei cycles between tsetse fly and mammalian hosts, and it is adapted to survive in diverse host tissues. Variant Surface Glycoprotein (VSG) plays a key role in immune evasion in the mammalian host. The VSG membrane anchor requires two myristates, 14-carbon saturated fatty acids (FAs) that are scarce in the host. T. brucei can synthesize FAs de novo, but also readily takes up exogenous FAs, despite lacking homologs to fatty acid uptake proteins found in other …

A Signal To Divide: Apoptotic Extracellular Vesicles As Carriers Of Mitogenic And Immunogenic Signals, Safia Essien, Safia Essien

Dissertations & Theses (Open Access)

Efficient replacement of dead cells in epithelial tissue is crucial for maintaining barrier function and tissue homeostasis. Apoptotic cells can signal to neighboring cells to stimulate proliferation and compensate for cell loss and maintain overall cell numbers in normal physiology and cancer. While dying cells can transmit instructive cues to neighboring cells, the molecular mechanisms that induce cell division are not well understood. Recent evidence suggests that apoptotic bodies (ABs) or apoptotic extracellular vesicles (AEVs) mediate cell-to-cell communication and carry diverse biologically active cellular cargo which can influence cell proliferation. This dissertation visualizes and characterizes AEVs in larval zebrafish and …

Genomic Characterization Of Adolescent And Young Adult Cancers: Investigation Of Ewing Sarcoma Susceptibility And Chornobyl Thyroid Tumors, Olivia Lee

Dissertations & Theses (Open Access)

Adolescent and young adult (AYA) cancers, diagnosed between the ages of 15 and 39, can exhibit distinctive genetic and molecular characteristics. Reported epidemiologic findings and treatment outcomes based on pediatric and adult cancer studies are often not suitable for application to the AYA population, underscoring the need for more thorough genomic research. Advances in sequencing technologies have enabled comprehensive analyses of complex genomic characteristics of AYA cancers, crucial for understanding the underlying biology of these malignancies. Here, I have utilized advanced sequencing techniques and integrated analytic approaches to describe important genomic features in two different AYA cancer types: Ewing Sarcoma …

Role Of The Immune System In The Modulation Of The Mmr-Deficient Intestinal Stem Cell Niche, Shepard Conner

Dissertations & Theses (Open Access)

Mismatch Repair (MMR) is a crucial DNA repair system to maintain genomic integrity in cells that is integrated by specific genes including MLH1, MSH2, MSH6, and PMS2. These genes play a critical role in repairing errors that occur in base pairing by stabilizing the genetic material. When the MMR system fails to correct those errors, MMR deficiency occurs where monoallelic mutations in the MMR genes result in a condition known as Lynch Syndrome (LS). LS makes up approximately 3% of all colorectal cancer (CRC) and is regarded as a hereditary form of CRC, which progresses from MMR-deficient …

Amyloid Fibrils Of Human Fgf-1 Induced By Different Detergents, Zeina Ismael Ibrahem Alraawi

Graduate Theses and Dissertations

Nature achieves molecular self-assembly through the ordered growth of nanoscale building blocks with high efficiency to fabricate macromolecular architectures. One example of self- assembly is peptides folding onto protein is one of the most astounding biological self-assembly processes. When proteins aggregate to form amyloid fibers, the secondary structure of the protein converts from its native state to a cross-beta-sheet. Fibroblast growth factors (FGFs) possess an essential role in neuronal survival during development. In addition, they are involved in neural stem cell (NSC) proliferation. Fibroblast growth factors (FGFs) are well known to be synthesized in the central nervous system (CNS) and …

Oncogenic Kras And Telomere Biology In Crc Progression, Ronald Depinho

Dissertations & Theses (Open Access)

While colorectal cancer (CRC) patients diagnosed with localized stage disease (as defined by SEER) have a 5-year survival rate of 90%, this rate plunges to 14% for patients diagnosed with metastatic CRC. Consequently, there is an immediate imperative to elucidate the mechanisms that drive the transition to advanced CRC.

Human CRCs carrying oncogenic mutations in the KRAS oncogene, henceforth referred to as KRAS*, exhibit a 25% higher propensity for developing liver metastases. Similarly, in our CRC mouse model, engineered with an inducible Kras* transgene and conditional null alleles of Apc and Tp53 (referred to as iKAP), KRAS* has been …

Cellular Mechanism Of Pentagalloyl Gucose-Mediated Prevention And Reversal Of Abdominal Aortic Aneurysms, Greg Halsey

All Dissertations

Abdominal aortic aneurysm (AAA) has been the 15th leading cause of death in persons older than 55 for the past ten years in several Western countries, with rupture resulting in an almost 100% mortality rate. AAA is a focal dilation of the aorta characterized by progressive loss of elastin and vascular smooth muscle cells (SMCs), as well as persistent inflammatory response [1]. The only treatment for AAA is surgery; however, the mortality post-procedure is still 1-4%, with a 15-30% chance of morbidity [2].

Pentagalloyl glucose (PGG) treatment is effective in the reversal of AAA. While its stabilizing interactions with extracellular …

Repositioning Propranolol To Block Mitogenic Signaling In Breast Cancer, Alexa Noel Montoya

Open Access Theses & Dissertations

Breast cancer is the second most diagnosed cancer among women and is about 30% of all new cases of female cancers each year. It is projected that 1 in 8 every U.S. woman (about 13%) develop invasive breast cancer over the course of her lifetime. While advances in cancer research have made it possible to elucidate several breast cancer genomic subtypes, and develop new novel therapies, many of these agents are associated with significant toxicity, as well as high costs. A retrospective cross-sectional study of 404 breast cancer patients was performed to determine the effect of β-blocker usage on tumor …

Characterization Of Developmental Phenotypes In Zebrafish With Mutations In Mmachc, Briana Elise Pinales

Open Access Theses & Dissertations

Methylmalonic aciduria and homocystinuria, CblC type (cblC) syndrome (MIM 277400) is a genetic disorder resulting from a mutation in the MMACHC gene. This gene plays a crucial role as a chaperone in the conversion of vitamin B12 into its active form, which is essential for proper cellular metabolism. cblC syndrome is heterogenous by nature, primarily attributed to the extensive damage it causes across multiple bodily systems. In cases of early onset of cblC syndrome, patients may exhibit a diverse range of clinical symptoms including difficulties with feeding, dysmorphic features, microcephaly, brain abnormalities, hypotonia, developmental delays, and seizures. The study of …

Breaking Virulent: The Coincidental Evolution Of Virulence Factors In Bacteria., Rhiannon Emmanuelle Cecil

Electronic Theses and Dissertations

Understanding how innocuous organisms can evolve to be pathogenic to humans is of increasing global concern. Further, understanding how existing pathogens may evolved to be more virulent is also vital to our ability to provide healthcare to people afflicted with diseases that promote chronic bacterial infections, such as cystic fibrosis. With the rise of antibiotic resistance in both bacteria and fungi it is paramount that new therapeutics are identified. Understanding what mutations occur that result in increased virulence in microbes can potentially provide new targets for antimicrobial drugs to combat antibiotic resistance. The Coincidental Evolution Hypothesis is a fundamental hypothesis …

Protein Trafficking In The Endoplasmic Reticulum Mediated By A Tpr-Containing Adapter Protein, Nathan P. Canniff

Doctoral Dissertations

The endoplasmic reticulum (ER) is a large, multifunctional organelle that acts as the entrance into the secretory pathway, which accounts for the folding and maturation of approximately one third of the human proteome. It is the largest organelle in most cell types and is comprised of a single lumen and a contiguous membrane. The ER is responsible for a multitude of roles including protein translocation, folding, maturation, quality control, and glycosylation to name a few. These processes are buoyed by a large collection of chaperones and cochaperones, the largest subfamily of which is characterized by the presence of tetratricopeptide repeat …

Caulobacter Clpxp Adaptor Popa’S Domain Interactions In The Adaptor Hierarchy Of Ctra Degradation, Thomas P. Scudder

Masters Theses

The degradation and recycling of protein is a process essential for the maintenance and regulation of cellular function. More specifically, in Caulobacter crescentus, the ClpXP protease is responsible for driving progression through the cell cycle and protein quality control. This protease utilizes three known adaptors to selectively degrade proteins that initiate different stages of development. This thesis will elaborate on the specific binding interface on one of these adaptors, PopA, with another, RcdA, and focus in on specific residues on PopA and investigate their roles in adaptor binding and delivery of CtrA, the master regulator of Caulobacter. Finally, I …

Pcbp1 Regulates Lifr Through Fam3c To Maintain Breast Cancer Stem Cell Self-Renewal And Invasiveness, William S. Streitfeld

MUSC Theses and Dissertations

The poly(rC) binding protein 1 gene (PCBP1) encodes the heterogenous nuclear ribonucleoprotein E1 (hnRNPE1), a nucleic acid-binding protein that plays a tumor-suppressive role in mammary epithelial cells by regulating phenotypic plasticity and cell fate. Following the loss of PCBP1 function, the FAM3C gene (encoding the Interleukin-like EMT inducer, or “ILEI” protein) and the leukemia inhibitory factor receptor (LIFR) gene are upregulated. Interaction between FAM3C and LIFR in the extracellular space induces phosphorylation of signal transducer and activator of transcription 3 (pSTAT3). Overexpression and/or hyperactivity of STAT3 has been detected in 40% of breast cancer cases and is associated with a …

The Adaptor Protein P66shc Governs Central Nervous System Cell Metabolism And Resistance To Aβ Toxicity, Asad Lone

Electronic Thesis and Dissertation Repository

Alzheimer’s disease (AD), a progressive and irreversible neurodegenerative disorder, and is the leading cause of dementia worldwide. It has been posited that AD is caused by the gradual deposition of toxic amyloid-b (Ab) plaques in the brain- that cause oxidative stress and eventually leads to neuronal death and synaptic loss. However, multiple therapies that either interfere with the production, or enhance the removal of Ab from the brain, have ultimately failed to slow or prevent AD. With the ever-increasing burden of AD worldwide, there exists an urgent need for novel therapeutic targets. The adult human brain is an energy demanding …

Early Development Of C3ar1-Targeting Chimeric Antigen Receptor T Cells For The Treatment Of Glioblastoma Multiforme, Cameron Fraser

Electronic Theses, Projects, and Dissertations

Glioblastoma multiforme is the most aggressive type of glioma, demonstrating extremely low long-term survival despite modern therapies. Chimeric antigen receptor T cells have shown extreme levels of success in the treatment of B cell lymphomas through persistent anti-tumor activity. Prior research has demonstrated the therapeutic potential in targeting the C3a-C3aR1 pathway as it acts in an autocrine loop, maintaining the proliferation and survival of cancer stem cells within the tumor. Here, we reorient the treatment to target C3aR1 for the treatment of glioblastoma multiforme. In order to achieve this, Jurkat immortalized T cells will express various chimeric antigen receptor designs …

Structural Insights Into The Cl-Par-4 Protein: Ionic Requirements, Conformational Transitions, And Interaction With Cisplatin, Krishna Kumar Raut

Chemistry & Biochemistry Theses & Dissertations

Cancer continues to be the leading global cause of death, with challenges in early diagnosis, drug resistance, non-specific drug targeting, and cancer recurrence and metastasis posing formidable obstacles in cancer therapy. In this context, Prostate Apoptosis Response-4 (Par-4), a pro-apoptotic tumor suppressor protein, emerged as a promising therapeutic target due to its ability to selectively induce apoptosis in cancer cells, thereby minimizing the drug-associated adverse effects. However, a comprehensive understanding of the structural features of Par-4, specifically the caspase-cleaved fragment (cl-Par-4), is crucial for therapeutic advancements.

This dissertation investigated the effects of various ions, both monovalent and divalent, on the …

Modified Vaccine Vectors To Understand Adjuvant Functions Of Listeria During Chronic Schistosomiasis, Stephanie K. Norwood

Biological Sciences Theses & Dissertations

Vaccination is one of the most effective strategies employed to prevent infectious diseases. Successful vaccination is dependent upon the induction of a specific, robust, and prolonged immune response. One of the major challenges faced by vaccine development is vaccine failure due to host-related factors that can modulate the immune system, which leads to non-responsiveness to vaccinations. The generation of new vaccine strategies is imperative to combat these effects. Live bacterial vectors are one approach used as they can elicit humoral immunity, cellular immunity, or both. Listeria monocytogenes is a Gram positive, intracellular pathogen that is an effective bacterial vaccine vector …

Oligodendrocyte 2phatal Reveals Dynamics Of Myelin Degeneration And Repair, Timothy W. Chapman

Dartmouth College Ph.D Dissertations

Oligodendrocytes are responsible for producing myelin in the central nervous system. This lipid-rich coating along axons helps to increase action potential velocity, provide metabolic support to axons, and facilitate fine-tuning of neuronal circuitry. Demyelination and/or myelin dysfunction is widespread in neurodegenerative diseases and aging. Despite this, we know very little about how individual oligodendrocytes, or the myelin sheaths they produce, degenerate. Myelin repair, carried out by resident oligodendrocyte precursor cells (OPCs), is known to occur following myelin damage in certain contexts. We sought to investigate the cellular dynamics of oligodendrocyte degeneration and repair by developing a non-inflammatory demyelination model, combining …

Exploring The Impact Of Pqn-75 And Glh-1/Vasa On Germline Development, Maintenance, And Gsc Reprogramming Using Caenorhabditis Elegans As A Model, Jesse D. Rochester

Electronic Theses and Dissertations

This thesis combines research on PQN-75 expression, functional motifs of GLH-1/Vasa, and germ granule components in Caenorhabditis elegans to provide a comprehensive understanding of germline development, maintenance, and reprogramming, while also examining the role of pharyngeal gland cells in stress resistance and thermotolerance. In C. elegans, pharyngeal gland cells secrete mucin-like proteins, such as PQN-75, with similarities to human PRB2. The expression of PQN-75 in gland cells confers stress resistance and thermotolerance but does not affect fertility, instead it plays a role in the organism's ability to adapt to varying environmental conditions. While, GLH-1/Vasa, an ATP-dependent DEAD-box helicase, plays …

A Quantitative Visualization Tool For The Assessment Of Mammographic Risky Dense Tissue Types, Margaret R. Mccarthy

Electronic Theses and Dissertations

Breast cancer is the second most occurring cancer type and is ranked fifth in terms of mortality. X-ray mammography is the most common methodology of breast imaging and can show radiographic signs of cancer, such as masses and calcifcations. From these mammograms, radiologists can also assess breast density, which is a known cancer risk factor. However, since not all dense tissue is cancer-prone, we hypothesize that dense tissue can be segregated into healthy vs. risky subtypes. We propose that risky dense tissue is associated with tissue microenvironment disorganization, which can be quantified via a computational characterization of the whole breast …

Muscle Defects Lead To Skeletal Deformities In A Zebrafish Model Of Distal Arthrogryposis, Emily A. Tomak

Electronic Theses and Dissertations

Distal Arthrogryposis Type 1 (DA1) involves mild muscle weakness and limb skeletal abnormalities thought to be caused by paralysis in utero. Why the limbs are particularly affected in DA1 and the degree of paralysis that leads to these skeletal deformities in utero remains unclear. Several muscle genes are known to cause DA1, including MYLPF (myosin light chain phosphorylatable), which encodes a myosin light chain protein that binds close to the force-generating head of myosin heavy chains. The zebrafish mylpfa^-/- mutant displays a phenotype consistent with DA1, including impaired myosin activity, reduced muscle force overall, and complete fin paralysis. I …

Endothelial Interleukin-17 Receptor D (Il17rd) Promotes Western Diet-Induced Aortic Myeloid Cell Infiltration, Shivangi Pande

Electronic Theses and Dissertations

The Interleukin-17 (IL17) family is a group of cytokines implicated in the etiology of several inflammatory diseases. Interleukin-17 receptor D (IL17RD), also known as Sef (similar expression to fibroblast growth factor), belonging to the family of IL17 receptors, has been shown to modulate IL17A-associated inflammatory phenotypes. The objective of this study was to test the hypothesis that IL17RD promotes endothelial cell activation and consequent monocyte adhesion. We utilized primary human aortic endothelial cells and demonstrated that RNAi targeting of IL17RD suppressed transcript levels by 83% compared to non-targeted controls. Further, RNAi knockdown of IL17RD decreased the adhesion of THP-1 cells …

Dynamics Of Site Search Process And Formation Of Synaptosome Assembly Characterized By Single Molecule Approaches, Sridhar Vemulapalli

Theses & Dissertations

Genome dynamics and integrity are the two crucial features defining the successful functioning of cells and their maintenance and evolution. The genetic processes in the cell require distant communications between the regulatory regions controlled by specific proteins. Mistakes in this interaction process will lead to termination of the genetic process may lead to the cell damage, disease development or the cell death. Similar distant regulatory process is required for numerous genome integration systems such as Variable Diversity Joining (V(D)J) recombination system resulting in the specificity of the immunoresponse, a defining property of the adaptive immune system. A common feature of …

Analyzing Pseudomonas Aeruginosa With Bacteriophage Tags Using Photoacoustic Flow Cytometry, Jennifer C. Schinke

Electronic Theses and Dissertations

The number of daily bacterial infections is climbing and the CDC explains that this is due to the antibiotic-resistant threat in the United States. Finding a faster way of bacterial identification is necessary as it currently takes 1-4 days for a medical lab to culture and identify bacteria. Photoacoustic flow cytometry (PAFC) can be used as an alternative method resulting in swift identification within an hour (Edgar, 2019). Pseudomonas aeruginosa, cell line PA01, will be coated in up to a few hundred red dyed phages making it detectible by the photoacoustic flow cytometry system. Bacteriophages (phages) are viruses that …

Selective Activation Of Thrombin Activatable Fibrinolysis Inhibitor (Tafi) Attenuates Metastatic And Angiogenic Capabilities Of Melanoma And Lung Carcinoma In Vitro, Jacklyn Krizsan

Electronic Thesis and Dissertation Repository

Metastasis and angiogenesis are hallmarks of aggressive cancers, both depending on degradation of extracellular matrix by proteases such as plasmin. Plasmin activation is inhibited by thrombin-activatable fibrinolysis inhibitor (TAFI)-mediated cleavage of terminal lysine residues on plasminogen receptors. Activation of TAFI is most effectively done in complex with thrombomodulin (TM). TM is known to have anti-cancer properties, but it is not known if this is due to TAFI activation or an alternative substrate protein C (PC). We hypothesize that specific promotion of TAFI activation with TM treatment will attenuate metastatic and angiogenic capabilities of tumour cells.

Melanoma and lung carcinoma cells …

A Comparison Of Pm-Nato3’S Influence On Neural Progenitors And Mature Dopamine Neurons, Mary E. West

Masters Theses

This thesis presents significant findings regarding the role of PM-Nato3 in its interaction with developing neurons in the context of Parkinson's disease (PD) and regenerative medicine. We investigated the effects of PM-Nato3 on dopamine (DA) neurogenesis under different culture conditions, both in vitro and in vivo. In the standard dopaminergic culture condition, PM-Nato3 potentially increased the speed of DA neuron production but did not significantly increase the yield of DA neurons. In a minimal culture condition, there was no notable difference between the control and PM-Nato3 conditions, suggesting minimal impact on DA neurogenesis. In vivo studies using a mouse model …

Investigating The Role Of Il-10 Producing Nkt Cells In Prevention Of Graft Versus Host Disease, Drew Boagni

Dissertations & Theses (Open Access)

The standard curative treatment for hematologic malignancies is allogeneic stem cell transplantation (ASCT), in which the patient’s immune system is replaced with that of a healthy donor. This can lead to cure through the graft versus leukemia (GVL) effect but can also cause graft versus host disease (GVHD), which is characterized by systemic inflammation and organ damage mediated by dysregulated donor T cells. Preclinical studies have shown invariant natural killer T cells (iNKT) cells can prevent GVHD while preserving GVL. iNKT cells are unconventional T cells which recognize glycolipid antigens presented in the context of CD1d. Upon activation, they secrete …