Nutrition Commons^™

Investigating Therapeutic Strategies To Target Metabolic Vulnerabilities Of Nsclc Tumors With Mutant Keap1 Gene, Pranavi Koppula

Dissertations & Theses (Open Access)

The metabolic vulnerability of cancers has long been envisaged as an attractive window to develop novel therapeutic strategies. Metabolic flexibility at the cellular level encompasses the efficient rerouting of anabolic and catabolic pathways in response to varying environmental stimuli to maintain cellular homeostasis and sustain proliferation. The primary objective of this study is to identify metabolic vulnerabilities bestowed by KEAP1/NRF2 signaling axis through SLC7A11. SLC7A11 is a transcriptional target of NRF2, an essential regulator of cellular anti-oxidant response. Under unstressed basal conditions, NRF2 interacts with KEAP1, a tumor suppressor gene and a substrate adaptor protein of the Cullin3-dependent ubiquitin ligase …

Unraveling Host-Gut Microbiota Dialogue And Its Impact On Response To Immune Checkpoint Blockade, Alexandria Cogdill

Dissertations & Theses (Open Access)

Cancer is a disease with only one degree of separation, affecting one in two men and one in three women in their lifetimes; accounting for 1 of every 6 deaths. While cancer mortality rates continue to improve, incidence rates are expected to rise and shift through 2050 due to epidemiological and demographic transitions worldwide. As such, it is imperative to continue to investigate and improve our understanding of both disease etiology and hallmarks of response to treatment. Currently, conventional therapies include, but are not limited to, surgery, chemotherapy, and radiotherapy. However, within the past decade, major advances have been made …

Ionic Mechanism Of Lysosomal Function And Cell Metabolism, Jian Xiong

Dissertations & Theses (Open Access)

Two Pore Channels (TPCs) are endolysosomal ion channels that are permeable to sodium and calcium. Defects in TPCs have been implicated to impair vesicle trafficking, autophagy and cell metabolism control; however, the detailed mechanism remains largely unknown. In this study, I show that TPCs are critical for appropriate cargo delivery to the lysosomes and deletion of either TPC1 or TPC2 leads to delayed clearance of autophagosomes, resulting in enlarged lysosomes and accumulated contents inside the lysosomes. Cells with both TPC deleted also exhibit 50% reduction in lysosomal amino acids under normal culture conditions, leading to reduced homeostatic mTORC1 activation.

Glutamine …

Platiscity Of C. Elegans Germline Stem Cells Under Nutritional And Metabolic Stress, Kenneth Trimmer

Dissertations & Theses (Open Access)

Stem cells are integral for tissue maintenance and fertility. Therefore, understanding how stem cells are regulated under stress is imperative. When confronted with acute starvation, stem cells must conserve energy and metabolites to cope with the lack of an external source. Caenorhabditis elegans germline stem cells (GSCs) are an excellent model for studying stem cell properties and regulation as they can divide throughout the life of the organism. While GSCs are an adult stem cell population, their cell cycle structure more closely mimics mouse and human embryonic stem cells with short G1 and long S phases. In this thesis, I …

Clinical And Therapeutic Significance Of Obesity In Melanoma, Jennifer L. Mcquade

Dissertations & Theses (Open Access)

While the FDA approval of targeted and immune therapies in metastatic melanoma (MM) have dramatically improved outcomes in this disease, de novo and/or acquired resistance can limit the clinical benefit of these agents. The IGF-1/PI3K/AKT pathway has been implicated in resistance to both targeted and immune therapy. The IGF-1/PI3K/AKT pathway has also been shown to play a key role in the pathogenesis of obesity in other malignancies. To date, the impact of energy balance on clinical outcomes and therapeutic response in MM has not been studied. I hypothesized that energy balance would impact the molecular biology, behavior, and drug sensitivity …

Acceleration Of The Panin Development In Mice Expressing Oncogenic K-Ras Due To A High Fat Diet, Bincy Philip

Dissertations & Theses (Open Access)

Obesity is postulated to be one of the major risk factors for pancreatic cancer, and recently it was indicated that an elevated body mass index (BMI correlates strongly with a decrease in patient survival. Despite the evident relationship, the molecular mechanisms involved are unclear. Oncogenic mutation of K-Ras is found early and is universal in pancreatic cancer. Extensive evidence indicates oncogenic K-Ras is not entirely active and it requires a triggering event to surpass the activity of Ras beyond the threshold necessary for a Ras-inflammation feed-forward loop. We hypothesize that high fat intake induces a persistent low level inflammatory response …

Targeting Akt/Mtor Signaling Pathways During Murine Skin Tumor Promotion And The Impact Of Dietary Energy Balance Manipulation, Laura A. Checkley

Dissertations & Theses (Open Access)

The prevalence of obesity has continued to rise over the last several decades in the United States lending to overall increases in risk for chronic diseases including many types of cancer. In contrast, reduction in energy consumption via calorie restriction (CR) has been shown to be a potent inhibitor of carcinogenesis across a broad range of species and tumor types. Previous data has demonstrated differential signaling through Akt and mTOR via the IGF-1R and other growth factor receptors across the diet-induced obesity (DIO)/CR spectrum. Furthermore, mTORC1 is known to be regulated directly via nutrient availability, supporting its role in the …