Cell and Developmental Biology Commons^™

Determination Of The Functional Role Of Rab-Ggt In Physcomitrium Patens., Hyun Jin Jung

Electronic Theses and Dissertations

Protein prenylation, a common lipid post-translational modification, is required for growth and development in eukaryotes. Rab geranylgeranylation involves the addition of one or two 20-carbon geranylgeranyl moieties to Rab-GTPase target proteins, which regulate intracellular vesicle trafficking. The reaction is carried out by heterodimeric Rab geranylgeranyltransferase (Rab-GGT), which is composed of two associated α- and β-subunits, with the assistance of an additional protein called Rab escort protein (REP). Loss of function of the Rab-GGT α subunit RGTA1 has not been reported in any plant. While knockout of either of the two β subunits RGTB1 or RGTB2 results in …

Regulation Of Systemic And Cellular Metabolism In Prostate Cancer By Camkk2 And Elucidation Of Atgl’S Role In Disease Progression, Dominik Awad

Dissertations and Theses (Open Access)

The androgen receptor (AR) is the major driver of prostate cancer; hence, men with progressing disease are treated with androgen deprivation therapy (ADT). However, the majority of patients will relapse within 2-3 years due to multiple AR reactivation mechanisms. Thus, AR and the processes downstream of the receptor remain central drivers of prostate cancer. A direct target of AR is CAMKK2, a gene coding for the serine/threonine kinase Ca^2+/calmodulin-dependent protein kinase kinase 2 (CAMKK2), a protein upregulated in advanced prostate cancer. CAMKK2 modulates many of its pathological effects through the phosphorylation and activation of the 5' AMP-activated …

Grk3 Connects Angiogenesis And Neuroendocrine Differentiation In Prostate Cancer By Activating Hdac2 That Epigenetically Represses Tsp1 And Rest, Samira Naderinezhad

Dissertations and Theses (Open Access)

Prostate cancer (PCa) is the second most frequent cancer and the second leading cause of mortality in men in the United States. Neuroendocrine prostate cancer (NEPC) is the aggressive subset of castration-resistant prostate cancer (CRPC), found in ~20% lethal CRPC. The mechanisms underlying the progression of PCa to NEPC are still largely unclear, and new drug targets are desperately needed. NEPC is highly vascularized (angiogenic) and characterized by high expression of neuroendocrine markers. However, direct molecular links connecting angiogenesis and neuroendocrine differentiation are elusive.

Since epigenetic regulation has been implicated in NEPC progression, we examined expression patterns of 147 epigenetic …

Genomewide Crispr/Cas9 Screen Identifies Network Of Protein Complexes That Regulate Trim24, Lalit Patel

Dissertations and Theses (Open Access)

TRIM24 is an oncogenic chromatin reader that is frequently overexpressed in human tumors and associated with poor prognosis. However, TRIM24 is rarely mutated, duplicated, or rearranged in cancer. This raises questions about how TRIM24 is regulated and whether changes in its regulation are responsible for its activity in cancer.

To investigate this possibility, I performed a genomewide CRISPR/Cas9 screen library using fluorescence activated cell sorting (FACS) to identify regulators of TRIM24. The screen was enabled by two innovations. I engineered cells with an in-frame knock-in of mClover3 to the endogenous copy of TRIM24 to allow fluorescent monitoring of TRIM24 expression …

Yap And Taz Are Required For Neural Crest-Derived Cardiovascular Development, Shannon Erhardt

Dissertations and Theses (Open Access)

Congenital heart defects (CHDs) are the most common human birth defect, occurring in ~1/100 newborns, and are a leading cause of early infant death. Cardiac neural crest cells (NCCs) are a migratory and multipotent cell population known to aid in the development of the cardiac outflow tract (OFT), valves, and interventricular septum, during embryogenesis. Yap and Taz are downstream effectors of the fundamental Hippo signaling pathway and are vital for proper organ and tissue development, yet their role in neural crest (NC)-derived heart formation is still largely unknown. We generated Yap and Taz conditional knockout (CKO) mice using a Cre-lox …

The Role Of The Hypoxia-Inducible Factor 2 In Pancreatic Cancer: Mechanisms Of Tumor Immunosuppression And Intestinal Radioprotection, Carolina Garcia Garcia

Dissertations and Theses (Open Access)

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with dismal prognosis. The only curative option for patients is surgery, but over 80% of patients are not surgical candidates. Unfortunately, PDAC is resistant to the three remaining options. PDAC is characterized by a profoundly hypoxic and immunosuppressive stroma, which contributes to its therapeutic recalcitrance. Alpha-smooth muscle actin+ (αSMA+) cancer-associated fibroblasts (CAFs) are the most abundant stromal component, as well as mediators of stromal deposition. The hypoxia-inducible factors (HIF1 and HIF2) coordinate responses to hypoxia, yet, despite their known association to poor patient outcomes, their functions within the PDAC tumor microenvironment (TME) …

Roles Of Oxidative Stress And Dna Methylation In Cigarette Smoking-Induced Accelerated Acute Myeloid Leukemia Progression, Mary Figueroa

Dissertations and Theses (Open Access)

Acute myeloid leukemia (AML) is a commonly diagnosed cancer in smokers. When current or former smokers have AML, they have worse survival compared to never smoking patients. This has been observed clinically for decades, but then it is unknown how smoking leads to worsened AML survival. Smoking causes oxidative stress and altered DNA methylation that persists for decades in peripheral blood mononuclear cells, but these changes from smoking have not been evaluated in the context of AML. We hypothesize that smoking-induced molecular changes, including altered DNA methylation associated with poor AML prognosis, promote AML. We developed a novel model to …

Non-Photic Mechanisms Of Entrainment In Bmal1 Deficient Conditions, Jamie Tran

Dissertations and Theses (Open Access)

Maintaining our internal circadian (i.e. 24 -hour) clock is imperative to our daily biological and mental well-being. Large epidemiological studies have shown that disruptions of our circadian rhythms can lead to poor mental health, metabolic diseases, and various types of cancer. Various external cues that have become a part of the modern times such as electricity, shift -work, rapid travel across various time zones, easier access to nutritionally unbalanced food items, and various rigid social demands have deleterious effects on our internal clock, and generally reduce robustness of the circadian clock. The two following projects aim to examine two fundamental …

The Novel Role Of Dnmbp In Kidney Development, Brandy Walker

Dissertations and Theses (Open Access)

Congenital anomalies of the kidney and urinary tract (CAKUT) accounts for nearly one-fourth of all birth defects and more than 40% of pediatric end-stage renal disease, yet only 10-20% of CAKUT cases have a known monogenetic cause. Human kidneys are composed of up to a million epithelial tubules called nephrons. Disruption of nephron development is one of the many congenital anomalies that cause CAKUT, often resulting in chronic or end-stage renal disease which requires transplant. During nephron epithelialization, the formation of stable cadherin-mediated adhesion junctions is essential for maintaining cell-cell contacts. To understand the cell behaviors underlying abnormalities in renal …

Heat Stress Response And Excystation In Entamoeba Histolytica, Irem Bastuzel

All Dissertations

Entamoeba histolytica is a water- and food-borne intestinal protozoan parasite that causes amoebiasis and liver abscess and is responsible for symptomatic disease in approximately 100 million people each year leading to ~ 100,000 deaths. The most common disease transmission follows the oral-fecal route, but it can also be transmitted by mechanical vectors such as animals carrying the amoeba from contaminated sources to water systems. In rare cases, disease transmission has been recorded in some patients in which men-to-men sexual practices were preferred.

The life cycle of E. histolytica starts through ingestion of infectious cysts, which are non-dividing, quadri-nucleated structures surrounded …

Neonatal Islet-1+ Cardiovascular Progenitor Cell-Derived Exosomes And Their Functional Ability To Regulate Proliferation, Lourdes Ceja

Electronic Theses, Projects, and Dissertations

Heart failure affects many people around the world and can lead to disease progression and death. Consequently, new stem and exosome-based therapies are needed to address this major health issue and to provide therapeutic options that will improve outcomes for the increasing number of patients with heart disease. Stem cell-derived exosomes have captivated researchers’ attention over the past couple of years based on their functional role in cellular signaling which highlights the vital component of the secretome of stem and progenitor cells. Since neonates have significantly enhanced regenerative ability, we hypothesized that exosomes isolated from Islet-1+ expressing neonatal human cardiovascular …

Sex Differences In Cancer Cachexia And A Novel Mitochondrial Target For Cancer-Induced Muscle Wasting, Seongkyun Lim

Graduate Theses and Dissertations

Cancer cachexia (CC) is a devastating wasting syndrome characterized by marked weight loss including skeletal muscle atrophy that affects approximately 80% of cancer patients. Current therapeutic treatments including pharmacological and nutritional intervention are insufficient to prevent or reverse it. Prior studies demonstrated lower muscle mass, impaired muscle function, and mitochondrial health in the development of CC. Specifically, mitochondrial fusion protein, Optic atrophy 1 (OPA1) which plays a significant role in skeletal muscle health, is suppressed in the development of CC. Furthermore, most pre-clinical CC studies were mainly focused on males although there are distinct phenotypical differences in skeletal muscle between …

Investigating Conserved Mechanisms For Embryonic Eye Regrowth In Xenopus Laevis, Cindy Kha

UNLV Theses, Dissertations, Professional Papers, and Capstones

Regeneration is a complex process to replace or restore tissue after damage. However, animals vary in their ability to regenerate tissue, and humans are limited in their abilities. Understanding how regeneration occurs in highly regenerative vertebrates, such as in Xenopus laevis frogs will lead to defining common regeneration mechanisms. In recent years, eye regeneration research in Xenopus laevis tadpoles provided new promising insight into the mechanisms necessary for repair of damaged eye tissue. Much progress has been made towards understanding the regenerative capability of the complex eye since Xenopus tadpoles can regenerate mature eye tissues, including: the optic nerve, retina, …

Screening Tcf19 And Kif18b To Determine Co-Regulation With Mybl1 In Triple Negative Breast Cancer Patient Tissues, Tyra Sharda Ivory

Theses (2016-Present)

The aggressive behavior in triple-negative breast cancer (TNBC) is due to genetic signaling events, which call for the comprehensive analyses of genes differentially regulated in the cancers. Our laboratory previously found that MYBL1 was over-expressed in a fraction of the TNBC, compared to some luminal, and other breast cancer subtypes. The MYBL1 gene is a proto-oncogene that serves as a strong transcriptional activator. The gene is involved in signaling events related to cell cycle signaling, differentiation, proliferation, and apoptosis, all which are differentially regulated in cancers. Because MYBL1 is a transcription regulator, involved in cancer-related mechanisms and differentially expressed in …

The Roles Of Epithelial–Mesenchymal Plasticity In Tumor Heterogeneity, Metastasis, And Patient Survival In Breast Cancer, Meredith Septer Brown

Dartmouth College Ph.D Dissertations

The Epithelial-to-Mesenchymal transition, a critical cellular process in development, is frequently co-opted by solid tumors to promote invasion and metastasis. In particular, the hybrid or intermediate EMT state, possessing both epithelial and mesenchymal characteristics, is associated with increased cancer stemness and plasticity. Similarly, intra-tumoral heterogeneity in solid tumors, in particular breast cancer, is associated with poor prognosis, tumor growth, proliferation, drug resistance, and metastasis. We sought to understand the link between the generation of intra-tumoral heterogeneity and the intermediate EMT state and their impact on tumor progression and patient prognosis. As part of my thesis work, I developed a model …

Novel Functions For Arp2/3 Complex-Mediated Actin Networks Discovered In Chlamydomonas Reinhardtii, Brae M. Bigge

Dartmouth College Ph.D Dissertations

Chlamydomonas reinhardtii, a unicellular member of the Chlorophyta or Green Algae phylum, has been used for decades as a model for ciliary studies. Using this tool, previous work from our lab found a role for actin in ciliary assembly and maintenance. However, while the microtubule-based, membrane-ensheathed cilia of Chlamydomonas are highly conserved in relation to mammalian cells, the actin cytoskeleton is not as simple. Chlamydomonas contains two actin genes: IDA5, a conventional actin, and NAP1, a divergent actin. Here, we find that despite the divergence of NAP1, it is still able to interact with the actin nucleator, the Arp2/3 complex. …

A Conserved Mechanism For Hormesis In Molecular Systems, Sharon N. Greenwood, Regina G. Belz, Brian P. Weiser

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Hormesis refers to dose-response phenomena where low dose treatments elicit a response that is opposite the response observed at higher doses. Hormetic dose-response relationships have been observed throughout all of biology, but the underlying determinants of many reported hormetic dose-responses have not been identified. In this report, we describe a conserved mechanism for hormesis on the molecular level where low dose treatments enhance a response that becomes reduced at higher doses. The hormetic mechanism relies on the ability of protein homo-multimers to simultaneously interact with a substrate and a competitor on different subunits at low doses of competitor. In this …

In Vivo Evaluation Of (-)-Zampanolide Demonstrates Potent And Persistent Antitumor Efficacy When Targeted To The Tumor Site., Leila Takahashi-Ruiz, Joseph D Morris, Phillip Crews, Tyler A Johnson, April L Risinger

Natural Sciences and Mathematics | Faculty Scholarship

Microtubule-stabilizing agents (MSAs) are a class of compounds used in the treatment of triple-negative breast cancer (TNBC), a subtype of breast cancer where chemotherapy remains the standard-of-care for patients. Taxanes like paclitaxel and docetaxel have demonstrated efficacy against TNBC in the clinic, however new classes of MSAs need to be identified due to the rise of taxane resistance in patients. (-)-Zampanolide is a covalent microtubule stabilizer that can circumvent taxane resistance in vitro but has not been evaluated for in vivo antitumor efficacy. Here, we determine that (-)-zampanolide has similar potency and efficacy to paclitaxel in TNBC cell lines, but …

Renal Cell Carcinoma Of Pelvic Kidney With Atypical Nodal Metastasis: A Diagnostic Challenge, Roshan-E-Shahid Rana, Muhammad Hammad Ather

Section of Urology

Ectopic pelvic kidney is a known congenital anomaly; however, the presence of renal cell carcinoma (RCC) in an ectopic kidney is rare with the evidence available in the form of a few case reports only. In this case report, we present a case of metastatic RCC in the pelvic kidney which became a diagnostic challenge because of atypical contrast-enhanced computed tomographic (CT) characteristics and unusual pattern of lymph node involvement including cervical lymph node in the absence of visceral metastasis. Because of its unusual location and uncertain vascular anatomy, ectopic kidney poses a surgical challenge. Owing to the rarity of …

Genome-Wide Characterization Of Salmonella Typhimurium Genes Required For The Fitness Under Iron Restriction, Sardar Karash, Tieshan Jiang, Young Min Kwon

Poultry Science Faculty Publications and Presentations

Background

Iron is a crucial element for bacterial survival and virulence. During Salmonella infection, the host utilizes a variety of mechanisms to starve the pathogen from iron. However, Salmonella activates distinctive defense mechanisms to acquire iron and survive in iron-restricted host environments. Yet, the comprehensive set of the conditionally essential genes that underpin Salmonella survival under iron-restricted niches has not been fully explored.

Results

Here, we employed transposon sequencing (Tn-seq) method for high-resolution elucidation of the genes in Salmonella Typhimurium (S. Typhimurium) 14028S strain required for the growth under the in vitro conditions with four different levels of iron …

Characterization Of The Responses To Chronic Stress In Caenorhabditis Elegans, Amy Laura Knight

Theses and Dissertations

Exposure to chronic temperature stress influences organismal phenotypes that are important for human health, agriculture, and ecology. In this thesis, the model organism Caenorhabditis elegans was used to study the effects of temperature stress on reproduction and lifespan. It was found that worms demonstrated a rapid shut down in egg-laying between 18-24 hours of exposure to 28°C. Despite this reproductive defect, the overall lifespan of worms was unaffected. At the molecular level, heat shock factor 1 (HSF-1), a regulator of the protective molecular pathway known as the heat shock response (HSR), was identified as important for progeny production during heat …

Regulation Of The Heat Shock Response Via Lysine Acetyltransferase Cbp-1 And In Neurodegenerative Disease In Caenorhabditis Elegans, Lindsey N. Barrett

USF Tampa Graduate Theses and Dissertations

The decline of proteostasis is a hallmark of aging that is, in part, affected by the dysregulation of the heat shock response (HSR), a highly conserved cellular response to proteotoxic stress in the cell. The heat shock transcription factor HSF-1 is well-studied as a key regulator of proteostasis, but mechanisms that could be used to modulate HSF-1 function to enhance proteostasis during aging are largely unknown. In this study, we examined lysine acetyltransferase regulation of the HSR and HSF-1 in C. elegans. We performed an RNA interference screen of lysine acetyltransferases and examined mRNA expression of the heat-shock inducible gene …

Increasing The Resilience Of Plant Immunity To A Warming Climate, Jong Hum Kim, Christian Castroverde, Shuai Huang, Chao Li, Richard Hilleary, Adam Seroka, Reza Sohrabi, Diana Medina-Yerena, Bethany Huot, Jie Wang, Sharon Marr, Mary Wildermuth, Tao Chen, John Macmicking, Sheng Yang He

Biology Faculty Publications

Extreme weather conditions associated with climate change affect many aspects of plant and animal life, including the response to infectious diseases. Production of salicylic acid (SA), a central plant defence hormone, is particularly vulnerable to suppression by short periods of hot weather above the normal plant growth temperature range via an unknown mechanism. Here we show that suppression of SA production in Arabidopsis thaliana at 28 °C is independent of PHYTOCHROME B (phyB) and EARLY FLOWERING 3 (ELF3), which regulate thermo-responsive plant growth and development. Instead, we found that formation of GUANYLATE BINDING PROTEIN-LIKE 3 (GBPL3) defence-activated biomolecular condensates (GDACs) …

Deciphering Phosphoprotein Phosphatase Signaling Networks Using Proteomics Approaches, Brooke Brauer

Dartmouth College Ph.D Dissertations

Protein phosphorylation is a highly regulated mechanism of cell signaling control and its deregulation is implicated in disease. The kinases that catalyze the addition of phosphate groups onto their substrate proteins have been well studied, their signaling pathways mapped, and their effects on cell and organismal health observed. Knowledge of the phosphatases that reverse the reaction only recently began to come into focus. Phosphoprotein phosphatases (PPPs), long thought to be housekeeping enzymes, are now known to be exquisitely specific towards their substrates, but the exact nature of phosphatase regulation—both upstream and downstream of the phosphatase—is unclear.

PPPs recognize substrates through …

Trends In Utilization Of Human Papillomavirus Vaccines And The Incidence Of Malignant Cervical Cancer In The U.S. Population: A Secondary Analysis, Myah Luna, Soumya Upadhyay

Healthcare Administration and Policy Faculty Research

Background: Human papillomavirus (HPV) is a sexually transmitted infection, and HPV types 16 and 18 are responsible for approximately 66% of all U.S. cervical cancer cases in women. The quadrivalent HPV vaccine was licensed in mid-2006, and it was designed to target and protect against HPV types 6, 11, 16, and 18. The aim of this study is to examine the utilization rate of the HPV vaccine, and the trends and incidence rate of malignant cervical cancer across the United States. Methods: This study utilized data from Surveillance, Epidemiology, and End Results (SEER) and the National Immunization Survey's (NIS) teenage …

The Molecular Mechanism Of Load Adaptation By Branched Actin Networks, Tai-De Li, Peter Bieling, Julian Weichsel, R Dyche Mullins, Daniel A. Fletcher

Advanced Science Research Center

Branched actin networks are self-assembling molecular motors that move biological membranes and drive many important cellular processes, including phagocytosis, endocytosis, and pseudopod protrusion. When confronted with opposing forces, the growth rate of these networks slows and their density increases, but the stoichiometry of key components does not change. The molecular mechanisms governing this force response are not well understood, so we used single-molecule imaging and AFM cantilever deflection to measure how applied forces affect each step in branched actin network assembly. Although load forces are observed to increase the density of growing filaments, we find that they actually decrease the …

Combined Curcumin And Luteolin Synergistically Inhibit Colon Cancer Associated With Notch1 And Tgf-Β Signaling Pathways In Cultured Cells And Xenograft Mice, Rukayat Aromokeye, Hongwei Si

Human Sciences Faculty Research

This study aimed to select a combination of curcumin and luteolin, two phytochemicals from food, at lower concentrations with a higher inhibitory effect on colon cancer growth and investigate possible molecular mechanisms of this anti-colon cancer effect. By pairwise combination screening, we identified that the combination of curcumin (CUR) at 15 μM and luteolin (LUT) at 30 μM (C15L30) synergistically suppressed the proliferation of human colon cancer CL-188 cells, but the individual chemicals had a little inhibitory effect at the selected concentrations. This result was also confirmed in other colon cancer DLD-1cells, suggesting that this synergistic inhibitory effect of C15L30 …

Investigating Roles Of 2 Novel Eklf Targets Involved In Erythropoiesis, Rose M. Gott

ETD Archive

Erythrocytes are primarily comprised of the oxygen carrying protein hemoglobin. Genetic mutations causing defects in the proper synthesis of hemoglobin result in various anemias. It is during the last phases of terminal erythroid differentiation that hemoglobin levels rise, making it a focus for therapeutic research. Fetal hemoglobin is comprised of ⍺-globin and gamma globin, then after a change in gene expression called hemoglobin switching which takes place after birth, adult hemoglobin is comprised of ⍺-globin and beta globin. We investigated hemoglobin switching and erythroid terminal differentiation by focusing on the master erythroid transcription factor Erythroid Krüppel-like Factor (EKLF). Data led …

Bio-Vascular 3d, Wisdom Shadrach

ORBioM (Open Research BioSciences Meeting)

Cardiovascular disease is a leading cause of mortality and morbidity across the world and according to the world health organization account for 32% of mortality rate globally. There still remain a need to develop better in vitro vascular models that would aid further in-depth understanding of cardiovascular pathogenesis and proposed therapeutic intervention.

This study intends to characterize four novel medically relevant synthetic polymer scaffolds, and one hydrogel, for their biocompatibility and potential application in a tissue engineered blood vessel (TEBV). A primary human endothelial cell line derived from the vein of the umbilical cord (HUVEC), and a human primary smooth …

Short Chain Fatty Acid Combination Treatment Protects Against 6-Ohda Induced Decrease In Neurite Growth In An In Vitro Model Of Parkinson’S Disease., Alex Morris

ORBioM (Open Research BioSciences Meeting)

Title: Short chain fatty acid combination treatment protects against 6-OHDA induced decrease in neurite growth in an in vitro model of Parkinson’s disease.

Authors: Alex Morris¹, Louise M. Collins^1,2,3, Gerard W. O’Keeffe², Caitriona M. Guinane¹

¹ Department of Biological Sciences, Munster Technological University (MTU), Cork, Ireland.

² Department of Anatomy & Neuroscience, University College Cork, Cork, Ireland.

³ Department of Physiology, University College Cork, Cork, Ireland.

Background: Parkinson’s disease (PD) is a neurodegenerative disorder characterized by dopaminergic neuron degeneration. This leads to motor dysfunction which is accompanied by gastrointestinal comorbidities such as constipation …