Medicine and Health Sciences Commons^™

Mutant Kras Alters Extracellular Vesicle Microrna Sorting In Pancreatic Cystic Neoplasms, Rachel L. Dittmar

Dissertations & Theses (Open Access)

Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest cancers by organ site with a 5-year survival rate of just 10.8%. This is largely because most patients do not experience symptoms until the disease has already metastasized. The best hope to cure PDAC is surgery, which can only be done with a curative intent at an early stage when the disease is localized. There are no reliable circulating, body-fluid-based biomarkers to detect early stage PDAC or its precursor lesions in a timely manner for effective surgical intervention. When potential PDAC precursor lesions, such as mucinous pancreatic cysts are found, there are …

Deciphering The Role Of Hsp110 Chaperones In Diseases Of Protein Misfolding, Unekwu M. Yakubu

Dissertations & Theses (Open Access)

Molecular chaperones maintain protein homeostasis (proteostasis) by ensuring the proper folding of polypeptides. Loss of proteostasis has been linked to the onset of numerous neurodegenerative disorders including Alzheimer’s, Parkinson’s, and Huntington’s disease. Hsp110 is a member of the Hsp70 class of molecular chaperones and acts as a nucleotide exchange factor (NEF) for Hsp70, the preeminent Hsp70-family protein folding chaperone. Hsp110 promotes rapid cycling of ADP for ATP, allowing Hsp70 to properly fold nascent or unfolded polypeptides in iterative cycles. In addition to its NEF activity, Hsp110 possesses an Hsp70-like substrate binding domain (SBD) whose biological roles are undefined. Previous work …

Understanding The Pathogenesis Of Renal Medullary Carcinoma, Melinda Soeung

Dissertations & Theses (Open Access)

Renal medullary carcinoma (RMC) is a lethal cancer that predominantly affects young individuals with sickle cell trait (SCT). It is not currently understood why RMC only affects certain individuals with SCT. We found that patients with RMC more frequently participated in high-intensity exercise than matched controls. Using mouse models of SCT, we demonstrated the significant increase of renal hypoxia in the right kidney following high- but not moderate-intensity exercise. We also demonstrated in cell culture studies that SMARCB1 is ubiquitinated for proteasome-mediated degradation in hypoxia, and the re-expression of SMARCB1 leads to compromised proliferation in renal cells specifically in the …

Epithelial Memory Of Resolved Inflammation Limits Tissue Damage While Promoting Pancreatic Tumorigenesis, I-Lin Ho

Dissertations & Theses (Open Access)

Inflammation is a major risk factor for pancreatic ductal adenocarcinoma. When occurring in the context of pancreatitis, mutations of KRAS accelerate tumor development. We discovered that long after its complete resolution, a transient inflammatory event primes pancreatic epithelial cells to subsequent transformation by oncogenic KRAS. Upon recovery from acute inflammation, epithelial cells of the pancreas display an enduring adaptive response associated with sustained transcriptional and epigenetic reprogramming. Such adaptation enables the prompt reactivation of acinar-to-ductal metaplasia (ADM) upon subsequent inflammatory events, thus efficiently limiting tissue damage via rapid decrease of zymogen production. We propose that since activating mutations of KRAS …

Understanding The Role Of Arglu1 In Interferon Signaling Activation In Breast Cancer, Phuoc Nguyen

Dissertations & Theses (Open Access)

In the U.S., the highest number of new cancer cases belongs to breast cancer in women, and this cancer also bears the second-highest death rate in women. Despite significant progress in breast cancer treatment that has been made in the past several decades, innovative and efficient therapies are still needed to eradicate this deadly disease. Novel cancer immunotherapy with immune checkpoint blockade (ICB) could induce long-lasting responses and improve survival in hard-to-treat malignancies. Regrettably, only a fraction of breast cancer patients respond to this highly promising strategy. To improving ICB therapy in breast cancer treatment, IFN signaling induction is a …

Targeting Plasma Membrane Phosphatidylserine Content To Inhibit Oncogenic Kras Function, Walaa E. Kattan

Dissertations & Theses (Open Access)

The small GTPase KRAS, which is frequently mutated in human cancers, must be localized to the plasma membrane (PM) for biological activity. We recently showed that the KRAS C-terminal membrane anchor exhibits exquisite lipid-binding specificity for select species of phosphatidylserine (PtdSer). We therefore investigated whether reducing PM PtdSer content is sufficient to abrogate KRAS oncogenesis. Oxysterol-related binding proteins ORP5 and ORP8 exchange PtdSer synthesized in the ER for phosphatidylinositol-4-phosphate (PI4P) synthesized in the PM. We show that depletion of ORP5 or ORP8 reduced PM PtdSer levels, resulting in extensive mislocalization of KRAS from the PM. Concordantly, ORP5 or ORP8 depletion …

Functions Of Dcp2 And Ski7 In Mrna Degradation, Minseon Kim, Ambro Van Hoof

Dissertations & Theses (Open Access)

Posttranscriptional gene regulation is essential to maintain gene expression fidelity. This is partially achieved by mRNA decay. When no longer required, mRNA is degraded by two alternative pathways. The decapping enzyme Dcp2 removes the 5` <sup>m7</sup>G cap of mRNAs, allowing Xrn1 to degrade the mRNA from the 5` end. Alternatively, mRNA is degraded from the 3` end by the RNA exosome.

While decapping by Dcp2 is a critical step in mRNA decay, its physiological function has been unclear. Null mutations of Saccharomyces cerevisiae DCP2 have been reported to be lethal in some studies but slow-growing in others. In this …

Rare Variant Association Studies In Crohn’S Disease And Colorectal Cancer: Methods And Applications, Jiun-Sheng Chen

Dissertations & Theses (Open Access)

Genetic factors account for a substantial portion of Crohn’s disease and colorectal cancer (CRC) risk. Patients with Crohn’s disease, a condition that causes chronic inflammation of the gastrointestinal tract, are at increased risk of colorectal cancer morbidity and mortality. Genome-wide association studies using single marker approaches have identified loci responsible for these diseases, but disease susceptibility from rare variants is incompletely understood. This dissertation includes three chapters, two association studies for Crohn’s disease and CRC, and a statistical method to improve the power of statistical tests.

For Crohn’s disease, we performed targeted sequencing of 101 genes in 205 children with …