Medicine and Health Sciences Commons^™

Proteostasis & Neuroinflammation In Alzheimer's Disease, Christa C. Huber

Dissertations and Theses

Alzheimer’s Disease (AD) is a devastating disorder with no disease-modifying agent that stops or reverses the progression of the disease. Exosomes, 50 – 150 nanometers in diameter extracellular vesicles, play a role in intracellular communication and are currently being explored as a therapeutic agent in various diseases. In addition, exosomes possess favorable characteristics as a therapy; however, their low yield following isolation hinders their ability as a therapeutic agent. We exposed neuroprogenitor cells to heat shock (HS) before exosomes were isolated to explore the possibility of increasing exosome secretion. HS-derived exosomes exhibit significantly increased concentration and diameter compared to non-heat …

Micro-Rna Analysis Of Extracellular Vesicles Secreted By Alveolar Macrophages And Epithelial Cells In Response To Cadmium, Anisha Bhakta

Biotechnology Theses

Inhalation of cadmium (Cd) has been an environmental health concern with the increase in industrial activities and smoking. Cd exposure is known to affect several organs such as lungs, kidneys, and liver. In this study, we wanted to understand if Cd inhalation exposure can affect the lungs and other organs in the body. Exosomes are extracellular vesicles secreted by all living cells and are known to carry toxicants between organs. We investigated whether Cd exposure could affect exosome biogenesis and their composition. Cd exposure did not affect the viability of A549, a lung epithelial cell line and macrophages derived from …

Development Of Long-Acting Antiviral Drug Nanoformulations, Denise Cobb

Theses & Dissertations

Antiretroviral therapy (ART) has improved the quality and duration of life for people living with human immunodeficiency virus (HIV) infection. However, opportunities to improve its profile abound. ART is limited by putative viral reservoir penetrance, emergence of viral mutations, inherent toxicities, and regimen non-adherence. These highlight the need improved drug delivery schemes. Previously, our lab has demonstrated that targeting mononuclear phagocytes for antiretroviral drug delivery extends drug half-life and improves penetrance into viral reservoirs, addressing these limitations of ART. Herein, we developed synthetic and biologic antiretroviral (ARV) drug nanocarriers improve the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of ARVs through …

Mechanisms And Therapeutic Interventions For Breast Cancer-Induced Fatigue And Mitochondrial Dysfunction, David Andrew Stanton

Graduate Theses, Dissertations, and Problem Reports

According to the latest statistics from the National Cancer Institute (NCI), about 1 in 8 U.S. women (~13%) will develop invasive breast cancer over the course of their lifetime. This translates to an estimated 268,600 new cases of breast cancer for the year 2019, and these diagnoses will collectively make up 15% of all new cancer cases across all cancer types. The majority of these women will experience the often-debilitating symptom of breast cancer-induced fatigue. these patients often have difficulty performing normal activities of daily living, have decreased tolerance to traditional tumor-directed therapies, and have higher rates of cancer recurrence. …

Exosomes Secreted Under Hypoxia Enhance Stemness In Ewing’S Sarcoma And Transform Microenvironment Cells, Matthew J. Kling

Theses & Dissertations

Intercellular communication between tumor cells and stroma within the hypoxic microenvironment promote aggressiveness and poor patient prognoses in ways that remain unclear. Here we show that hypoxic Ewing’s sarcoma (EWS) cells release exosomes that promote sphere formation, a stem-like phenotype, in EWS cells by enhancing survival and a cancer-associated phenotype in fibroblasts (CAFs). Given that hypoxia enriches for stem-like cells, we exposed EWS cells to hypoxia and hypoxic EWS-derived exosomes and assessed the stem cell phenotype. Hypoxia and hypoxic EWS-derived exosomewere found to enhance TIC formation in vitro and in vivo by reprogramming EWS cells. Analysis of the hypoxic exosomal …

Tumor-Derived Exosomes Drive Immunosuppressive Macrophages In A Pre-Metastatic Niche Through Nf-Kβ Dependent Glycolytic Metabolic Reprogramming., Samantha M. Morrissey

Electronic Theses and Dissertations

The formation of a pre-metastatic niche is a fundamental requirement for primary tumor metastasis. One of the defining characteristics of a pre-metastatic niche is infiltration of immunosuppressive macrophages. However, how these macrophages acquire their immunosuppressive phenotype remains largely unexplored. Here, we demonstrate that tumor-derived exosomes (TDE) polarize macrophages towards an immunosuppressive phenotype characterized by increased PD-L1 expression through NF-kB-dependent metabolic reprogramming in mice and humans. While NF-κB has previously been shown to act as a direct transcription factor for PD-L1, we report a novel mechanism where TDE-induced NF-κB activation drives PD-L1 expression by augmenting the glycolytic capacity of macrophages through …

Identification And Molecular Analysis Of Dna In Exosomes, Jena Tavormina

Dissertations & Theses (Open Access)

Exosomes are heterogeneous nanoparticles 50-150nm in diameter. Exosomes contain many functional cargo components, such as protein, DNA, and RNA. While protein and RNA exosome content has been extensively studied, very little work has been done to characterize exosomal DNA. Here, we demonstrate that exosomal DNA is heterogeneous and its packaging into exosomes is dependent on the cell of origin. Furthermore, through a rigorous assessment of various isolation methods, we identify Size Exclusion Chromatography (SEC) as the best method for the isolation of exosomal DNA for downstream applications. Additionally, we evaluate the methylation status of exosomal DNA and demonstrate that exosomal …

Conjugated Bile Acid And Sphingosine 1-Phosophate Prompt Cholangiocarcinoma Cell Growth Via Releasing Exosomes, Waad A. Alruwaili

Theses and Dissertations

Cholangiocarcinoma (CCA) is a fatal primary malignancy that is formed in the bile ducts. Cancer-associated myofibroblasts play a crucial role in CCA proliferation and invasion. Furthermore, there is a growing interest in the role of the exosome in the interaction between the cancer-associated myofibroblasts and cholangiocarcinoma which lead to CCA growth. However how cholangiocarcinoma-derived exosome affect the cancer-associated myofibroblasts in the tumor microenvironment remain unknown. In this study, we examined whether exosome produced by cholangiocarcinoma could involve in the prompt of CCA cells growth by regulation of myofibroblast. We found that cholangiocarcinoma-derived exosome could prompt elevated α-smooth muscle actin and …

Targeted Delivery Of A Therapeutic Protein For The Treatment Of Alzheimer's Disease, Heather Holman

Honors Undergraduate Theses

Neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease are linked to mitochondrial dysfunction and the underexpression of TOM40, a protein with chaperone-like qualities that is responsible for transporting precursor proteins into the mitochondria. Overexpression of TOM40 is reported to partially restore mitochondrial dysfunction and decrease the accumulation of neurotoxic aggregates of α-synuclein. Our goal is to develop an effective method for delivery of TOM40 protein to the brain.

Previous studies have used lentiviruses to carry TOM40 into the hippocampus of α-synuclein transgenic mice. The disadvantage of lentiviral transfection is the random insertions of the target gene into the host …

Parasympathetic Nerve Derived Exosomes Inhibit Hyperglycemia Induced Apoptosis In Cardiomyoblast Cells, Reetish K. Singla

Honors Undergraduate Theses

Diabetic cardiomyopathy involves both forms of cardiac cell cell death such as apoptosis and necrosis. However, this remains unknown whether hyperglycemia induced apoptosis in the cell culture system is inhibited by parasympathetic nerve derived exosomes. We isolated parasympathetic and sympathetic nerves and derived exosomes. We developed hyperglycemia induced apoptosis in H9c2 cells. H9c2 cells were divided into 4 groups: 1) Control, 2) H9c2+ Glucose 100 mmol, 3) H9c2+ Glucose +parasympathetic-exo, 4) H9c2+ Glucose+sympathetic-exo. We determined cell proliferation and viability with MTT assay kit and apoptosis with TUNEL staining and cell death detection ELISA kit. Data was further confirmed with pro-apoptotic …

Development Of Methods To Modulate Natural Killer Cells, Kari A. Shaver

Honors Undergraduate Theses

Natural Killer (NK) cell based immunotherapies have demonstrated success against malignancies and hematological cancers. However, tumors have developed mechanisms to evade detection by and suppress the immune system, commonly through altering the expression of cell-surface proteins. Overexpression of human leukocyte antigen-E (HLA-E), which binds to the inhibitory NKG2A on NK cells, protects malignant cells from lysis. Downregulating the NKG2A receptor on NK cells should release NK cell inhibition, but proves challenging as NK cells are difficult to transfect and no good methods currently exist. This project is designed to investigate the use of exosomes – small vesicles and natural carriers …

Exosomal Curcumin: Its Bioavailability And Potential Anti-Inflammation Activity, Dongmei Sun

All ETDs from UAB

Curcumin, a pleiotropic polyphenol derived from turmeric plants Curcuma Longa with rhizome, exhibits strong evidence as an anti-inflammation, anti-oxidant and anti-cancer reagent both in vitro and in vivo. Due to its low stability and systemic bioavailability, a large amount of curcumin has to be administrated to achieve therapeutic effects both in animal and in human. The major effort to overcome this barrier is making by encapsulation of curcumin into nanoparticles such as polymers and liposomes; some promising data have demonstrated the effectiveness of such method. Exosomes are vesicle-like nanoparticles secreted by living cells. Exosomes contain both cell surface molecules and …